Bu iş için destek Ulusal Sağlık hibe Enstitüleri tarafından sağlanan # R01 HL 108.229, Amerikan Kalp Derneği Scientist Kalkınma Hibe # 0830352N, Howard Hughes Tıp Enstitüsü Kariyer Geliştirme Ödülü, Broadview Ventures, Avrupa Topluluğunun Yedinci Çerçeve Programı (hibe altında FP7/2007-2013 anlaşma # 235.689) ve MGH William Schreyer Bursu.

In vivo Hayvan Modeli: Deneysel Aortoiliyak Ateroskleroz Üretimi 1) Temel Anjiyografi ve Balon denüdasyon <ol><li> Bazal anjiyografi ve balon denüdasyon elde etmek için önce, Yeni Zelanda beyaz tavşanı, yüksek kolesterol (% 1), 1 hafta boyunca diyet beslenir. Bu hayvan tavşanlarda aorto-iliacs damarları hiperlipidemik, balon-yaralanma modeli benzer inflamatuar hücreler (makrofajlar taşıyan iltihaplı ateroskleroz üretir insan koroner arterlerin (2.5-3.5mm) ve 2) aynı kalibre) 1 olarak translasyonel alaka için kullanılmaktadır insan ateroskleroz) ve molekülleri (katepsinler). </li><li> Kolesterol besleme, hayvan, propofol ve ketamin ile anestezi. Tek inç ventral orta hat boyun insizyonu bir boyutu 15 neşter bıçak kullanarak kullanılarak yapılır. Künt diseksiyon teknikleri kullanarak, trakeanın sağ tarafında fasya altındaki kasların maruz kalmaktadır. Sol sternocephalicus kas, bağ dokusu kavşak boyunca ayrılır ve sağ karotis arter maruz kalmaktadır. Arter vagus siniri ayrılır. Proksimal ve distal sütür döngüler retraksiyon ve oklüzyon için izin arter üzerine yerleştirilir. 1 2mm için arteriyotomi eğimli 5 Fransız (1.67mm dış çapı) vasküler kılıf takılı ve heparin (1000μ/mL ~ 150units/kg) kılıf ile intra-arteriyel uygulanan üzerinden yapılır. </li><li> Kontrast madde (Ultravist) sonra bir kontrol anjiyogram distal aorta ve her iki iliak arterlerden elde etmek için 2 saniyelik bir süre içinde (1 2mL) enjekte edilir. </li><li> Iliofemoral arter ve aort sonra endotelyal soyulma yaralandı. Standart floroskopi yöntemlerinin kullanılması, distal iliofemoral arter 3FR Fogarty embolektomi kateteri yerleştirilir ve 0,3 0,5 kontrast cc (% 50 tuzlu contrast/50%) ya da hava ile şişirildi. Kateter daha sonra kendi şişirilmiş devlet sol renal arter proksimalde take-off sağ iliyak ve distal aorta boyunca bir mesafe geri çekilir. Balon denüdasyon ardından, anjiyografi, damar açıklığının belge tekrarlanır. Anjiyografi sonrasında, tüm kateterler ve kılıflar kaldırılır ve proksimal sağ karotis arter ligasyonu, kas ve fasya 4 / 0 emilebilir sütür ile sütüre, ve cilt insizyonu 4 / 0 emilmeyen dikiş ile kapatıldı. </li><li> Hayvan daha sonra tek doz antibiyotik (sefazolin, 0.5 gram IM) yönetimi ile kurtarmak için izin verilir. Ağrı kesici ilaçlar da dahil olmak üzere 0.01 mg / kg buprenorfin IM (gerektiği kadar günde iki kez). Hayvanlar daha sonra, 4 hafta sonrası balon denüdasyon için% 1 kolesterol üzerinde devam etmektedir. Haftada 5, hayvanların% 0.3 kolesterol diyeti geçiş. </li></ol> Tavşan Atheromata Entegre Multi-modal Görüntüleme 2) proteolitik aktif iltihaplı plak enjektabl nanosensor kullanarak etiketleme; Anjiyografi, intravasküler ultrason (IVUS), ve in vivo intravasküler NIRF görüntüleme Tavşan Aterom <ol><li> Görüntüleme için önce balon yaralanma ve 24 saat sonra sekiz hafta, intravenöz 500 nmol / kg Prosense/VM110 (Perkin Elmer) ile tavşan kulak damar yoluyla enjekte edilir. </li><li> Yirmi dört saat, enjeksiyon sonrası hayvanlarda anestezi ve arteriyel erişimi (adım 1.2 &#39;ye bakınız), sol karotis arter yoluyla elde edilir. İntra-arteriyel heparin (150 ünite / kg) uygulanır. Temel anjiyografi yukarıdaki gibi elde edilir. </li><li> IVUS kateter bir klinik koroner arter yetenekli 0.014 inç tel üzerine yüklenir ve kılıf içine eklenir. Floroskopik kullanarak, tel radyoopak ucu sağ iliyak arter distalde bir konuma sahiptir. IVUS kateter sonra standart bir klinik monoray tekniği kullanılarak proksimal iliak artere ileri düzeydedir. </li><li> A 100 mm geri çekilme başlatılır ve görüntüleri kaydedilir. Geminin Boyuna rekonstrüksiyon elde edilir ve luminal plak tanımlanır. </li><li> NIRF kateter 11,12 0.014 inç tel (monoray sistemi) üzerine yüklenir ve sağ iliyak artere kateter dikkatle kılıf ve görüntüleme kafası takılı distalde konumlandırılmış. </li><li> Çoklu otomatik pullbacks (1 mm / sn boyuna geri çekilme, dakikada 30 mermi) yapılır ve ateroskleroz bölgeleri içinde floresan sinyalleri belirtilmiştir. Görüntü kaydedilir ve sinyal aralığı dayalı uygun ölçekleme ve pencereleme ile daha fazla işlem gerçekleştirilir. </li></ol> 3) Ötenazi ve ex vivo aorto-iliyak doku izolasyonu <ol><li> Ötenazi ötenazi ajan 1 cc (390mg sodyum pentobarbital ve 50 mg fenitoin sodyum çözümü), intravenöz, tek bir enjeksiyon ile gerçekleştirilir. </li><li> Inferior vena kava kan netleşene kadar arter ağacı% 0.9 serum fizyolojik ile perfüze. Aterosklerotik aorta ve iliak arterler tespit ve çevre dokulardan disseke vardır. Buna ek olarak, li küçük 2 x 2 cm adetver, böbrek, dalak ve kalp de elde edilir. </li><li> Intravasküler NIRF görüntüleme kateter ile ex vivo NIRF görüntüleme bu aşamada yapılabilir. Geminin uzun ve görüntüleme başı sağ iliyak arter veya çatallanma getirilinceye kadar NIRF kateter proksimal aort içine yeniden eklenir. Çoklu otomatik pullbacks (bkz 2.6) yukarıdaki gibi yapılır. </li></ol> 4) disseke aorta ve iliak arterlerden ex vivo Floresans Yansıtma Görüntüleme (CUMA) <ol><li> Disseke doku yerleştirilir ve 10-20 cc serum fizyolojik FRI analizleri (Kodak Görüntü İstasyonu 4000mm Pro, Carestream Health, Inc.) Taşınır. </li><li> Aorta, iliak damarlar yaklaşık gerçek zamanlı uzunlukları uzatılmış ve çoklu dalga boylarını [beyaz ışık, yeşil floresan kanal (eski 495 nm, em 515 nm), Cy5 (eski 565 nm, em 670 nm) ve Cy7 (eski görüntüler elde edilir 650 nm, em 760 nm)] kanal. Pozlama süreleri bir dizi her dalga boyu için kullanılmaktadır (0,1-30sn) ve elde edilen görüntüler DICOM ya da daha fazla analiz için 16-bit ölçeklendirilmemiş TIFF dosyaları olarak ihraç edilmektedir. Pozitif ve negatif kontroller olarak, organların (karaciğer, dalak, böbrek ve kalp) benzer kanalları ve pozlama süreleri görüntülü. </li><li> Yakın-kızılötesi kanal (780nm +) artış sinyali Alanları aterosklerotik arterlerde belirtilmiştir. </li></ol> Kesit ve immünhistokimyasal analiz için 5) Doku Gömme <ol><li> Alanları normal (olmayan yaralı doku, yani sol iliyak arter) ve plak alanlar tespit edilir ve doku küçük 5-10 mm halkaları OCT (Optimum Kesme Sıcaklık) medya gömülü. Bloklar kesit kadar -80 C&#39;de saklanır. </li><li> Kesit ve immünohistokimyasal analizler için standart teknikler yapılmaktadır. Hematoksilen ve eosin Ram-11 ve Katepsin B boyama yapılır, leke. </li></ol> Analizler ve multi-modal Görüntü Entegrasyonu (Anjiyografi, IVUS, NIRF ve CUMA) 6) NIRF ve CUMA görüntü İşleme <ol><li> DICOM NIRF ve CUMA görüntüleme verileri içeren dosyalar (yakın kızılötesi 780 nm kanal alınan) pullbacks sırasıyla, MATLAB ve Osirix yazılımı kullanarak işlenir. Uygun sinyal yoğunluğu tam kapsamlı görüntülemek için pencere elde edilir. Final görüntüleri TIFF dosyaları olarak ihraç edilmektedir. </li><li> Dosyalar standart görüntü işleme yazılımı (Davetli kullanılabilir) alınır. Görüntüler referans noktaları (anjiyogram, iliak bifurkasyon ve renal arter yani vertebra) göre hizalanır. Normal damar ve plak alanları belirlenmiştir. </li><li> Ilgi (ROI) Bölgeler elle takip (plak normal doku ve alanlar için) ve sinyal intensitesi CUMA ve NIRF görüntülerin her ikisi için de sırasıyla Osirix ve MATLAB kullanılarak elde edilen ortalama. Uygun izleme kılavuzu için, geminin boyuna IVUS görüntü kullanılır ve normal damar ve plak tanımlanması için kolayca tanınırlar. </li><li> Hedef arka plan (KAZ) oranları plak bölgeleri için hesaplanır. </li></ol> Temsilcisi Sonuçlar: Yukarıdaki protokol tamamlanmasından sonra, biz tanımlayabilir ve aorta ve iliak damarlar içinde inflamatuar plak artar katepsin proteaz faaliyet alanları karakterize. (Prosense/VM110) devreye sokulabilir nanosensor enjeksiyon bize proteolitik aktif plak tanımlamanıza olanak sağlar. Bu kadar parlak görünür ya da yakın kızılötesi kanal (750 nm) CUMA kullanarak görüntülü yoğun bölgeleri sinyal. NIRF pullbacks yüksek sinyal FRI yoğunluğu ve NIRF sinyalleri anatomik kaydı izin IVUS hizalanmalar ile ilişkilidir. CUMA ve NIRF elde Hesaplanan plak TBR (NIRF TBR 4.2 ortalama, CUMA TBR 2.9 ortalama bkz. Şekil 3) benzer bulunmuştur. Parlak plak immünohistokimyasal analizi, RAM-11 ve plak alanları (veri gösterilmemiştir) Katepsin B aktivitesi yoğun varlığını doğrulamaktadır. <img alt="Şekil 1" src="/files/ftp_upload/2257/2257fig1.jpg" /> Şekil 1. 11,12 özel dahili kateter bir optik fiber (125 mikron çaplı ev sahipliği oluşur 1D NIRF algılama yaklaşımı 6 klinik potansiyelini genişletmek için 2D NIRF Kateter şematik bir roman damar içi görüntüleme için 2-B NIRF kateter inşa edilmiştir. polietilen borular: 2.9F) 750 nm lazer uyarma kaynağı kullanarak aydınlatır. Lazer ışığı, lif eksenine göre 90 derecelik bir açıyla yayılır. Sistem gerçek 2D görüntü elde etmek için birlikte 360 ​​derece görüntüleme ve boyuna geri çekilme sağlamak için iki otomatik motorlar (rotasyon ve translasyon) kullanır. Görüntüler referans 11 izni ile kullanılır. <img alt="Şekil 2" src="/files/ftp_upload/2257/2257fig2.jpg" /> Şekil 2. Nanosensor şematik gösteren proteaz aracılı aktivasyon, Prosense/VM110. Referans 10 izni ile kullanılmaktadır Görüntü. <img alt="Tablo 1" src = &quot;/ files/ftp_upload/2257/2257table1.jpg&quot; /&gt; Şekil 3. In vivo ve ex vivo Plak TBRs (arka plan oranları hedef)

<ol>
	<li>Andersson, J., Libby, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Adaptive+immunity+and+atherosclerosis.">Adaptive immunity and atherosclerosis.</a> Clin Immunol. 134, 33-46 (2010).</li><li>Calfon, M. A., Vinegoni, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intravascular+near-infrared+fluorescence+molecular+imaging+of+atherosclerosis:+toward+coronary+arterial+visualization+of+biologically+high-risk+plaques.">Intravascular near-infrared fluorescence molecular imaging of atherosclerosis: toward coronary arterial visualization of biologically high-risk plaques.</a> Journal of Biomedical Optics. 15, 011107-011107 (2010).</li><li>Chen, J., Tung, C. -. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+Vivo+Imaging+of+Proteolytic+Activity+in+Atherosclerosis.">In Vivo Imaging of Proteolytic Activity in Atherosclerosis.</a> Circulation. 105, 2766-2771 (2002).</li><li>Jaffer, F. A., Libby, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Molecular+Imaging+of+Cardiovascular+Disease.">Molecular Imaging of Cardiovascular Disease.</a> Circulation. 116, 1052-1061 (2007).</li><li>Jaffer, F. A., Libby, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optical+and+Multimodality+Molecular+Imaging:+Insights+Into+Atherosclerosis.">Optical and Multimodality Molecular Imaging: Insights Into Atherosclerosis.</a> Arterioscler Thromb Vasc Biol. 29, 1017-1024 (2009).</li><li>Jaffer, F. A., Vinegoni, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Real-Time+Catheter+Molecular+Sensing+of+Inflammation+in+Proteolytically+Active+Atherosclerosis.">Real-Time Catheter Molecular Sensing of Inflammation in Proteolytically Active Atherosclerosis.</a> Circulation. 118, 1802-1809 (2008).</li><li>Kim, D. -. E., Kim, J. -. Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Protease+Imaging+of+Human+Atheromata+Captures+Molecular+Information+of+Atherosclerosis,+Complementing+Anatomic+Imaging.">Protease Imaging of Human Atheromata Captures Molecular Information of Atherosclerosis, Complementing Anatomic Imaging.</a> Arterioscler Thromb Vasc Biol. 30, 449-456 (2010).</li><li>Libby, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inflammation+in+atherosclerosis.">Inflammation in atherosclerosis.</a> Nature. 420, 868-874 (2002).</li><li>Naghavi, M., Libby, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=From+Vulnerable+Plaque+to+Vulnerable+Patient:+A+Call+for+New+Definitions+and+Risk+Assessment+Strategies:+Part+I.">From Vulnerable Plaque to Vulnerable Patient: A Call for New Definitions and Risk Assessment Strategies: Part I.</a> Circulation. 108, 1664-1672 (2003).</li><li>Weissleder, R., Tung, C. -. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vivo+imaging+of+tumors+with+protease-activated+near-infrared+fluorescent+probes.">In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.</a> Nat Biotech. 17, 375-375 (1999).</li><li>Razansky, R. N., Rosenthal, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Near-infrared+fluorescence+catheter+system+for+two-dimensional+intravascular+imaging+in+vivo.">Near-infrared fluorescence catheter system for two-dimensional intravascular imaging in vivo.</a> Optics Express. 18, 11372-11381 (2010).</li><li>Jaffer, F. A., Calfon, M. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Two-Dimensional+Intravascular+Near-Infrared+Fluorescence+Molecular+Imaging+of+Inflammation+in+Atherosclerosis+and+Stent-Induced+Vascular+Injury.">Two-Dimensional Intravascular Near-Infrared Fluorescence Molecular Imaging of Inflammation in Atherosclerosis and Stent-Induced Vascular Injury.</a> Journal of the American College of Cardiology. 57, 2516-2526 (2011).</li></ol>

FAJ - Eski Danışmanı, VisEn Tıp, Ücretler, Boston Scientific

Iltihaplı yüksek riskli ya da hassas plak, miyokard enfarktüsü çoğunluğu için muhtemelen sorumludur. Semptomların başlamasından önce bu plakların tanımlama sonuçlarını tahmin etmek ve tıbbi tedavinin yönlendirilmesinde önemli klinik hem de etkileri vardır. X-ray anjiyografi gibi konvansiyonel koroner arter görüntüleme yöntemleri genellikle luminal daralma karakterizasyonu ziyade, yüksek riskli non-stenotik lezyonlar genellikle altta yatan biyolojik profilleri aydınlatıcı odaklanmak. İntrava...

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<tr>
<td>Prosense 750</td>
<td>&nbsp;</td>
<td>Visen Medical</td>
<td>VM110</td>
<td>500 nmol/kg IV injection</td>
</tr>
<tr>
<td>Heparin Sodium</td>
<td>&nbsp;</td>
<td>APP Pharmaceuticals</td>
<td>401586D</td>
<td>&nbsp;</td>
<tr>
<td>Cephazolin</td>
<td>&nbsp;</td>
<td>NovaPlus</td>
<td>46015683</td>
<td>&nbsp;</td>
<tr>
<td>Lidocaine HCL 2%</td>
<td>&nbsp;</td>
<td>Hospira</td>
<td>NDC 0409-4277-01</td>
<td>&nbsp;</td>
<tr>
<td>Buprenorphine</td>
<td>&nbsp;</td>
<td>Bedford Laboratories</td>
<td>NDC 55390-100-10</td>
<td>&nbsp;</td>
<tr>
<td>Ketamine</td>
<td>&nbsp;</td>
<td>Hospira</td>
<td>NDC 0409-2051-05</td>
<td>&nbsp;</td>
<tr>
<td>High Cholesterol Diet 1%</td>
<td>&nbsp;</td>
<td>Research Diets</td>
<td>C30293</td>
<td>&nbsp;</td>
<tr>
<td>HIgh Cholesterol Diet 0.3%</td>
<td>&nbsp;</td>
<td>Research Diets</td>
<td>C30255</td>
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in vivo near infrared fluorescence (nirf) intravascular molecular imaging of inflammatory plaque, a multimodal approach to imaging of atherosclerosis

Yaralanma vasküler yanıt, lipid yüklü içi luminal plak, düz kas hücre proliferasyonu ve damar lümen daralması ilerici birikimi giden damar duvarının içinde makrofajların birikimi ile tetiklenen çok iyi yönetilen bir inflamatuar yanıt. Rüptürü altında yatan akut miyokard infarktüsü vakalarının çoğunluğu eğilimli gibi hassas plakların oluşumu. Karmaşık moleküler ve hücresel inflamatuar kaskad endotel ve düz kas hücreleri, T lenfositler ve makrofajlar ve parakrin etkileri işe yönetti. 1 Ateroskleroz Moleküler görüntüleme, enflamasyon ve diğer biyolojik süreçler in vivo görüntüleme sağlayan önemli bir klinik ve araştırma aracı haline gelmiştir . Son zamanlarda yaşanan bazı örnekler, yüksek riskli plaklar hastalarda tespit ve ateroskleroz pharmacotherapeutics etkilerini değerlendirmek için yeteneğini göstermek 4 moleküler görüntüleme yaklaşımları (özellikle MR ve PET) bir dizi biyolojik yönlerini karotis gibi büyük damarların görüntüsü arterler, koroner arterleri görüntüleme için yetersizdir seçenekleri var. 2 yüksek çözünürlüklü optik görüntüleme stratejileri gelişi, özellikle yakın-kızılötesi floresan (NIRF) devreye sokulabilir floresan problar ile birleştiğinde, gelişmiş hassasiyet ve yeni intravasküler stratejilerinin geliştirilmesi yol açtı insan koroner ateroskleroz biyolojik görüntüleme artırmak için. Kızılötesi floresan (NIRF) civarında moleküler görüntüleme, optik kontrast madde ya da floresan prob teslim tespit edilebilir NUR penceresinde floresan yayar, fotonların bir kaynak olarak belirli bir bant genişliği (650-900 nm) ile uyarma ışık kullanan uygun bir emisyon filtresi ve yüksek hassasiyet şarj çiftli kamera kullanarak. NUR ışık, görünür ışık aksine, doku içine derinlemesine nüfuz eder, hemoglobin, yağ ve su gibi endojen foton emiciler tarafından belirgin bir şekilde daha az zayıflatılmış ve NUR pencere azalmış otofloresans nedeniyle yüksek hedef-arka oranları sağlar. NUR &#39;penceresi içinde Görüntüleme in vivo görüntüleme için potansiyel önemli ölçüde artırabilir. 2,5 İnflamatuar sistein proteazlar aktive NIRF probları 10 kullanılarak çalışıldı ve aterogenezde önemli rol oynamaktadır edilmiştir. Ekstraselüler matriks bozulması ile, sistein proteazlar ilerlemesini ve komplikasyonları ateroskleroz 8 önemlisi katkıda bulunur. Özellikle, sistein proteaz, katepsin B, son derece olarak ifade edilir ve, deneysel Fare ve sıçan, tavşan ve insan atheromata makrofajlar ile colocalizes Ayrıca 3,6,7, plaklarda katepsin B aktivitesi önceden 1 açıklanan kullanarak in vivo olarak algılanır. -D ile birlikte birden fazla NUR fluorochromes (VM110/Prosense750, eski / em 750/780nm VisEn Tıp, Woburn, MA) ile derivatized poli-lizin polimer omurgası oluşan bir enjektabl nanosensor ajan intravasküler yakın-kızılötesi floresan teknolojisiyle 6 başlangıçta güçlü bir molekül su verme bu sonuçları 10 Aşağıda NIRF sinyal önemli amplifikasyon katepsin B (plak makrofajlar colocalize bilinen), ayrı fluorochromes sistein proteazlar tarafından enzimatik parçalanma hedef . İntravasküler kullanılan roman 2D intravasküler NIRF kateter NUR floresan sinyal algılama iltihaplı plak katepsin B aktivitesi in vivo algılama geometrik olarak doğru, yüksek çözünürlüklü sağlar. Ateroskleroz gibi önceden 1-D spektroskopik yaklaşımın aksine kateter tabanlı 2B NIRF görüntüleme, in vivo moleküler görüntüleme, 6 yeni ve umut verici bir araç vasküler inflamasyon tespit makrofaj zengin plak proteaz aktivitesi artar kullanır. 11,12 Aşağıdaki araştırma protokolü görüntü NIRF 2-boyutlu bir intravasküler kateter kullanımı açıklanır ve plak biyoloji temel yönlerini kullanarak plak yapısını karakterize. Bu, anjiyografi ve intravasküler ultrason (IVUS) da dahil olmak üzere mevcut klinik görüntüleme teknolojileri ile entegre bir çevrilebilir platform inflamatuar atheromata ayıran benzersiz ve yeni bir entegre multimodal moleküler görüntüleme tekniği sunuyor ve insan ölçekli koroner arterlerde intravasküler NIRF sinyallerin algılanmasını sağlar. .

Watch this Scientific Journal Video about In vivo Near Infrared Fluorescence NIRF Intravascular Molecular Imaging of Inflammatory Plaque, a Multimodal Approach to Imaging of Atherosclerosis at JoVE.co

In vivo Near Infrared Fluorescence NIRF Intravascular Molecular Imaging of Inflammatory Plaque, a Multimodal Approach to Imaging of Atherosclerosis

Biz, ayrıntılı 2-boyutlu plak biyoloji intravasküler moleküler görüntüleme için yeni bir yakın-kızılötesi floresan (NIRF) kateter<em&gt; In vivo</em&gt;. NIRF kateter varlığı plak hevesli devreye sokulabilir ve hedefli NUR fluorochromes raporlama inflamasyon gibi temel biyolojik süreçlerin oluşturulabiliyor. Kateter klinik mühendislik ve güç gereksinimleri kullanır ve insan koroner arterlerin uygulama için hedeflenen. Aşağıdaki araştırma çalışması bir roman kullanan bir multimodal görüntüleme stratejisi açıklanmıştır<em&gt; In vivo</em&gt; Intravasküler NIRF görüntü kateter ve proteolitik aktif iltihaplı tavşan atheromata inflamatuar plak ölçmek.

İnflamatuar Plak Kızılötesi Floresans (NIRF) İntravasküler Moleküler Görüntüleme, Multimodal Yaklaşım civarında in vivo Ateroskleroz Görüntüleme

The vascular response to injury is a well-orchestrated inflammatory response triggered by the accumulation of macrophages within the vessel wall leading ...

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In vivo Near Infrared Fluorescence (NIRF) Intravascular Molecular Imaging of Inflammatory Plaque, a Multimodal Approach to Imaging of Atherosclerosis

17.8K Görüntüleme.  Harvard Medical School. Biz, ayrıntılı 2-boyutlu plak biyoloji intravasküler moleküler görüntüleme için yeni bir yakın-kızılötesi floresan (NIRF) kateter In vivo. NIRF kateter varlığı plak hevesli devreye sokulabilir ve hedefli NUR fluorochromes raporlama inflamasyon gibi temel biyolojik süreçlerin oluşturulabiliyor. Kateter klinik mühendislik ve güç gereksinimleri kullanır ve insan koroner arterlerin uygulama için hedeflenen. Aşağıdaki araştırma çal?...

Video: In vivo Near Infrared Fluorescence NIRF Intravascular Molecular Imaging of Inflammatory Plaque, a Multimodal Approach to Imaging of Atherosclerosis

In vivo Dual Substrate Bioluminescent Imaging

Our understanding of how and when breast cancer cells transit from established primary tumors to metastatic sites has increased at an exceptional rate since the advent of in vivo bioluminescent imaging technologies 1-3. Indeed, the ability to locate and quantify tumor growth longitudinally in a single cohort of animals to completion of the study as opposed to sacrificing individual groups of animals at specific assay times has revolutionized how researchers investigate breast cancer metastasis. Unfortunately, current methodologies preclude the real-time assessment of critical changes that transpire in cell signaling systems as breast cancer cells (i) evolve within primary tumors, (ii) disseminate throughout the body, and (iii) reinitiate proliferative programs at sites of a metastatic lesion. However, recent advancements in bioluminescent imaging now make it possible to simultaneously quantify specific spatiotemporal changes in gene expression as a function of tumor development and metastatic progression via the use of dual substrate luminescence reactions. To do so, researchers take advantage for two light-producing luciferase enzymes isolated from the firefly (Photinus pyralis) and sea pansy (Renilla reniformis), both of which react to mutually exclusive substrates that previously facilitated their wide-spread use in in vitro cell-based reporter gene assays 4. Here we demonstrate the in vivo utility of these two enzymes such that one luminescence reaction specifically marks the size and location of a developing tumor, while the second luminescent reaction serves as a means to visualize the activation status of specific signaling systems during distinct stages of tumor and metastasis development. Thus, the objectives of this study are two-fold. First, we will describe the steps necessary to construct dual bioluminescent reporter cell lines, as well as those needed to facilitate their use in visualizing the spatiotemporal regulation of gene expression during specific steps of the metastatic cascade. Using the 4T1 model of breast cancer metastasis, we show that the in vivo activity of a synthetic Smad Binding Element (SBE) promoter was decreased dramatically in pulmonary metastasis as compared to that measured in the primary tumor 4-6. Recently, breast cancer metastasis was shown to be regulated by changes within the primary tumor microenvironment and reactive stroma, including those occurring in fibroblasts and infiltrating immune cells 7-9. Thus, our second objective will be to demonstrate the utility of dual bioluminescent techniques in monitoring the growth and localization of two unique cell populations harbored within a single animal during breast cancer growth and metastasis.

In vivo Dual Substrate Bioluminescent Imaging

Herein we describe the methods to construct, visualize, and quantify the bioluminescent reactions of both firefly and renilla luciferase enzymes expressed in metastatic breast cancer cells during their growth and metastasis in vivo.

Vivo Çift Yüzey Bioluminescent Imaging&#39;de

Our understanding of how and when breast cancer cells transit from established primary tumors to metastatic sites has increased at an exceptional rate ...

Tıp

Implantation of a Carotid Cuff for Triggering Shear-stress Induced Atherosclerosis in Mice

It is widely accepted that alterations in vascular shear stress trigger the expression of inflammatory genes in endothelial cells and thereby induce atherosclerosis (reviewed in 1 and 2). The role of shear stress has been extensively studied in vitro investigating the influence of flow dynamics on cultured endothelial cells 1,3,4 and in vivo in larger animals and humans 1,5,6,7,8. However, highly reproducible small animal models allowing systematic investigation of the influence of shear stress on plaque development are rare. Recently, Nam et al. 9 introduced a mouse model in which the ligation of branches of the carotid artery creates a region of low and oscillatory flow. Although this model causes endothelial dysfunction and rapid formation of atherosclerotic lesions in hyperlipidemic mice, it cannot be excluded that the observed inflammatory response is, at least in part, a consequence of endothelial and/or vessel damage due to ligation.
In order to avoid such limitations, a shear stress modifying cuff has been developed based upon calculated fluid dynamics, whose cone shaped inner lumen was selected to create defined regions of low, high and oscillatory shear stress within the common carotid artery 10. By applying this model in Apolipoprotein E (ApoE) knockout mice fed a high cholesterol western type diet, vascular lesions develop upstream and downstream from the cuff. Their phenotype is correlated with the regional flow dynamics 11 as confirmed by in vivo Magnetic Resonance Imaging (MRI) 12: Low and laminar shear stress upstream of the cuff causes the formation of extensive plaques of a more vulnerable phenotype, whereas oscillatory shear stress downstream of the cuff induces stable atherosclerotic lesions 11. In those regions of high shear stress and high laminar flow within the cuff, typically no atherosclerotic plaques are observed.
 
In conclusion, the shear stress-modifying cuff procedure is a reliable surgical approach to produce phenotypically different atherosclerotic lesions in ApoE-deficient mice.

The constricting cuff presented in this article is designed to induce atherosclerosis in the murine common carotid artery. Due to the conical shape of its inner lumen the implanted cuff generates well-defined regions of low, high and oscillatory shear stress triggering the development of atherosclerotic lesions of different inflammatory phenotypes.

Fare Shear stres İndüklenmiş Ateroskleroz Tetikleme Karotis Kol İmplantasyonu

It is widely accepted that alterations in vascular shear stress trigger the expression of inflammatory genes in endothelial cells and thereby induce ...

Molecular Imaging to Target Transplanted Muscle Progenitor Cells

Duchenne muscular dystrophy (DMD) is a severe genetic neuromuscular disorder that affects 1 in 3,500 boys, and is characterized by progressive muscle degeneration1, 2. In patients, the ability of resident muscle satellite cells (SCs) to regenerate damaged myofibers becomes increasingly inefficient4. Therefore, transplantation of muscle progenitor cells (MPCs)/myoblasts from healthy subjects is a promising therapeutic approach to DMD. A major limitation to the use of stem cell therapy, however, is a lack of reliable imaging technologies for long-term monitoring of implanted cells, and for evaluating its effectiveness. Here, we describe a non-invasive, real-time approach to evaluate the success of myoblast transplantation. This method takes advantage of a unified fusion reporter gene composed of genes (firefly luciferase [fluc], monomeric red fluorescent protein [mrfp] and sr39 thymidine kinase [sr39tk]) whose expression can be imaged with different imaging modalities9, 10. A variety of imaging modalities, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and high frequency 3D-ultrasound are now available, each with unique advantages and limitations11. Bioluminescence imaging (BLI) studies, for example, have the advantage of being relatively low cost and high-throughput. It is for this reason that, in this study, we make use of the firefly luciferase (fluc) reporter gene sequence contained within the fusion gene and bioluminescence imaging (BLI) for the short-term localization of viable C2C12 myoblasts following implantation into a mouse model of DMD (muscular dystrophy on the X chromosome [mdx] mouse)12-14. Importantly, BLI provides us with a means to examine the kinetics of labeled MPCs post-implantation, and will be useful to track cells repeatedly over time and following migration. Our reporter gene approach further allows us to merge multiple imaging modalities in a single living subject; given the tomographic nature, fine spatial resolution and ability to scale up to larger animals and humans10,11, PET will form the basis of future work that we suggest may facilitate rapid translation of methods developed in cells to preclinical models and to clinical applications.

A non-invasive means to evaluate the success of myoblast transplantation is described. The method takes advantage of a unified fusion reporter gene composed of genes whose expression can be imaged with different imaging modalities. Here, we make use of a fluc reporter gene sequence to target cells via bioluminescence imaging.

Nakledilen Muscle Progenitör Hücreler Hedefleyecek Moleküler Görüntüleme

Duchenne muscular dystrophy (DMD) is a severe genetic neuromuscular disorder that affects 1 in 3,500 boys, and is characterized by progressive muscle ...

In vivo Imaging of Tumor Angiogenesis using Fluorescence Confocal Videomicroscopy

Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite fluorescent in situ elements through the optical fibers, and then record some of the emitted photons, via the same optical fibers. The light source is a laser that sends the exciting light through an element within the fiber bundle and as it scans over the sample, recreates an image pixel by pixel. As this scan is very fast, by combining it with dedicated image processing software, images in real time with a frequency of 12 frames/sec can be obtained.
We developed a technique to quantitatively characterize capillary morphology and function, using a confocal fluorescence videomicroscopy device. The first step in our experiment was to record 5 sec movies in the four quadrants of the tumor to visualize the capillary network. All movies were processed using software (ImageCell, Mauna Kea Technology, Paris France) that performs an automated segmentation of vessels around a chosen diameter (10 &mu;m in our case). Thus, we could quantify the 'functional capillary density', which is the ratio between the total vessel area and the total area of the image. This parameter was a surrogate marker for microvascular density, usually measured using pathology tools.
The second step was to record movies of the tumor over 20 min to quantify leakage of the macromolecular contrast agent through the capillary wall into the interstitium. By measuring the ratio of signal intensity in the interstitium over that in the vessels, an 'index leakage' was obtained, acting as a surrogate marker for capillary permeability.

In vivo Imaging of Tumor Angiogenesis using Fluorescence Confocal Videomicroscopy

In this paper, we present a method to analyze tumor microvessels in vivo using dynamic contrast-enhanced fluorescence videomicroscopy. Two quantitative parameters were acquired: functional capillary density reflecting the vascularity of the tumor, and index leakage reflecting the leakiness of the endothelial wall.

Flüoresans Konfokal videomikroskopi kullanılarak tümör Angiogenesis İn vivo

Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite ...

A Human Ex Vivo Atherosclerotic Plaque Model to Study Lesion Biology

Atherosclerosis is a chronic inflammatory disease of the vasculature. There are various methods to study the inflammatory compound in atherosclerotic lesions. Mouse models are an important tool to investigate inflammatory processes in atherogenesis, but these models suffer from the phenotypic and functional differences between the murine and human immune system. In vitro cell experiments are used to specifically evaluate cell type-dependent changes caused by a substance of interest, but culture-dependent variations and the inability to analyze the influence of specific molecules in the context of the inflammatory compound in atherosclerotic lesions limit the impact of the results. In addition, measuring levels of a molecule of interest in human blood helps to further investigate its clinical relevance, but this represents systemic and not local inflammation. Therefore, we here describe a plaque culture model to study human atherosclerotic lesion biology ex vivo. In short, fresh plaques are obtained from patients undergoing endarterectomy or coronary artery bypass grafting and stored in RPMI medium on ice until usage. The specimens are cut into small pieces followed by random distribution into a 48-well plate, containing RPMI medium in addition to a substance of interest such as cytokines or chemokines alone or in combination for defined periods of time. After incubation, the plaque pieces can be shock frozen for mRNA isolation, embedded in Paraffin or OCT for immunohistochemistry staining or smashed and lysed for western blotting. Furthermore, cells may be isolated from the plaque for flow cytometry analysis. In addition, supernatants can be collected for protein measurement by ELISA. In conclusion, the presented ex vivo model opens the possibility to further study inflammatory lesional biology, which may result in identification of novel disease mechanisms and therapeutic targets.

A Human Ex Vivo Atherosclerotic Plaque Model to Study Lesion Biology

Atherosclerosis is a chronic inflammatory process. This manuscript illustrates an easy to use ex vivo model to investigate fresh carotid or coronary artery plaques. The ex vivo model allows for the investigation of potential substances on the inflammatory milieu in human atherosclerotic lesions and results can be analyzed by various methods.

Bir İnsan<em&gt; Ex Vivo</em&gt; Aterosklerotik Plak Model Lezyon Biyoloji Eğitim için

Atherosclerosis is a chronic inflammatory disease of the vasculature. There are various methods to study the inflammatory compound in atherosclerotic ...

Tissue-simulating Phantoms for Assessing Potential Near-infrared Fluorescence Imaging Applications in Breast Cancer Surgery

Inaccuracies in intraoperative tumor localization and evaluation of surgical margin status result in suboptimal outcome of breast-conserving surgery (BCS). Optical imaging, in particular near-infrared fluorescence (NIRF) imaging, might reduce the frequency of positive surgical margins following BCS by providing the surgeon with a tool for pre- and intraoperative tumor localization in real-time. In the current study, the potential of NIRF-guided BCS is evaluated using tissue-simulating breast phantoms for reasons of standardization and training purposes.
Breast phantoms with optical characteristics comparable to those of normal breast tissue were used to simulate breast conserving surgery. Tumor-simulating inclusions containing the fluorescent dye indocyanine green (ICG) were incorporated in the phantoms at predefined locations and imaged for pre- and intraoperative tumor localization, real-time NIRF-guided tumor resection, NIRF-guided evaluation on the extent of surgery, and postoperative assessment of surgical margins. A customized NIRF camera was used as a clinical prototype for imaging purposes.
Breast phantoms containing tumor-simulating inclusions offer a simple, inexpensive, and versatile tool to simulate and evaluate intraoperative tumor imaging. The gelatinous phantoms have elastic properties similar to human tissue and can be cut using conventional surgical instruments. Moreover, the phantoms contain hemoglobin and intralipid for mimicking absorption and scattering of photons, respectively, creating uniform optical properties similar to human breast tissue. The main drawback of NIRF imaging is the limited penetration depth of photons when propagating through tissue, which hinders (noninvasive) imaging of deep-seated tumors with epi-illumination strategies.

Near-infrared fluorescence (NIRF) imaging may improve therapeutic outcome of breast cancer surgery by enabling intraoperative tumor localization and evaluation of surgical margin status. Using tissue-simulating breast phantoms containing fluorescent tumor-simulating inclusions, potential clinical applications of NIRF imaging in breast cancer patients can be assessed for standardization and training purposes.

Meme Kanseri Cerrahisinde Potansiyel Yakın kızılötesi Floresans Görüntüleme Uygulamaları değerlendirilmesi için Phantom Doku-simüle

Inaccuracies in intraoperative tumor localization and evaluation of surgical margin status result in suboptimal outcome of breast-conserving surgery ...

Murine Endoscopy for In Vivo Multimodal Imaging of Carcinogenesis and Assessment of Intestinal Wound Healing and Inflammation

Mouse models are widely used to study pathogenesis of human diseases and to evaluate diagnostic procedures as well as therapeutic interventions preclinically. However, valid assessment of pathological alterations often requires histological analysis, and when performed ex vivo, necessitates death of the animal. Therefore in conventional experimental settings, intra-individual follow-up examinations are rarely possible. Thus, development of murine endoscopy in live mice enables investigators for the first time to both directly visualize the gastrointestinal mucosa and also repeat the procedure to monitor for alterations. Numerous applications for in vivo murine endoscopy exist, including studying intestinal inflammation or wound healing, obtaining mucosal biopsies repeatedly, and to locally administer diagnostic or therapeutic agents using miniature injection catheters. Most recently, molecular imaging has extended diagnostic imaging modalities allowing specific detection of distinct target molecules using specific photoprobes. In conclusion, murine endoscopy has emerged as a novel cutting-edge technology for diagnostic experimental in vivo imaging and may significantly impact on preclinical research in various fields.

Murine Endoscopy for In Vivo Multimodal Imaging of Carcinogenesis and Assessment of Intestinal Wound Healing and Inflammation

Small animal imaging techniques allow serial diagnostic examinations and therapeutic interventions in vivo. Recently, the scope of applications has significantly widened and currently includes assessment of colonic tumor development, wound healing and monitoring of inflammation. This protocol illustrates these diverse potential applications of murine endoscopy.

Murin için Endoskop<em&gt; In Vivo</em&gt; Karsinojenez ve bağırsak Değerlendirilmesi Multimodaller Görüntüleme Yara İyileşmesi ve İltihap

Mouse models are widely used to study pathogenesis of human diseases and to evaluate diagnostic procedures as well as therapeutic interventions ...

Validation of Nanobody and Antibody Based In Vivo Tumor Xenograft NIRF-imaging Experiments in Mice Using Ex Vivo Flow Cytometry and Microscopy

This protocol outlines the steps required to perform ex vivo validation of in vivo near-infrared fluorescence (NIRF) xenograft imaging experiments in mice using fluorophore labelled nanobodies and conventional antibodies.
First we describe how to generate subcutaneous tumors in mice, using antigen-negative cell lines as negative controls and antigen-positive cells as positive controls in the same mice for intraindividual comparison. We outline how to administer intravenously near-infrared fluorophore labelled (AlexaFluor680) antigen-specific nanobodies and conventional antibodies. In vivo imaging was performed with a small-animal NIRF-Imaging system. After the in vivo imaging experiments the mice were sacrificed. We then describe how to prepare the tumors for parallel ex vivo analyses by flow cytometry and fluorescence microscopy to validate in vivo imaging results.
The use of the near-infrared fluorophore labelled nanobodies allows for non-invasive same day imaging in vivo. Our protocols describe the ex vivo quantification of the specific labeling efficiency of tumor cells by flow cytometry and analysis of the distribution of the antibody constructs within the tumors by fluorescence microscopy. Using near-infrared fluorophore labelled probes allows for non-invasive, economical in vivo imaging with the unique ability to exploit the same probe without further secondary labelling for ex vivo validation experiments using flow cytometry and fluorescence microscopy.

Validation of Nanobody and Antibody Based In Vivo Tumor Xenograft NIRF-imaging Experiments in Mice Using Ex Vivo Flow Cytometry and Microscopy

This protocol outlines the steps required to perform ex vivo validation of in vivo near-infrared fluorescence xenograft imaging experiments in mice using fluorophore labelled nanobodies and conventional antibodies.

Nanobody ve Antikor Temelli Doğrulama<em&gt; İn Vivo</emFarelerde&gt; Tümör Xenograftlarında NIRF-görüntüleme Deneyler kullanma<em&gt; Ex vivo</em&gt; Sitometrisi ve Mikroskopi

This protocol outlines the steps required to perform ex vivo validation of in vivo near-infrared fluorescence (NIRF) xenograft imaging experiments in mice ...

Combined Near-infrared Fluorescent Imaging and Micro-computed Tomography for Directly Visualizing Cerebral Thromboemboli

Direct thrombus imaging visualizes the root cause of thromboembolic infarction. Being able to image thrombus directly allows far better investigation of stroke than relying on indirect measurements, and will be a potent and robust vascular research tool. We use an optical imaging approach that labels thrombi with a molecular imaging thrombus marker&#160;&#8212; a Cy5.5 near-infrared fluorescent (NIRF) probe that is covalently linked to the fibrin strands of the thrombus by the fibrin-crosslinking enzymatic action of activated coagulation factor XIIIa during the process of clot maturation. A micro-computed tomography (microCT)-based approach uses thrombus-seeking gold nanoparticles (AuNPs) functionalized to target the major component of the clot: fibrin. This paper describes a detailed protocol for the combined in vivo microCT and ex vivo NIRF imaging of thromboemboli in a mouse model of embolic stroke. We show that in vivo microCT and fibrin-targeted glycol-chitosan AuNPs (fib-GC-AuNPs) can be used for visualizing both in situ thrombi and cerebral embolic thrombi. We also describe the use of in vivo microCT-based direct thrombus imaging to serially monitor the therapeutic effects of tissue plasminogen activator-mediated thrombolysis. After the last imaging session, we demonstrate by ex vivo NIRF imaging the extent and the distribution of residual thromboemboli in the brain. Finally, we describe quantitative image analyses of microCT and NIRF imaging data. The combined technique of direct thrombus imaging allows two independent methods of thrombus visualization to be compared: the area of thrombus-related fluorescent signal on ex vivo NIRF imaging vs. the volume of hyperdense microCT thrombi in vivo.

This protocol describes the application of combined near-infrared fluorescent (NIRF) imaging and micro-computed tomography (microCT) for visualizing cerebral thromboemboli. This technique allows the quantification of thrombus burden and evolution. The NIRF imaging technique visualizes fluorescently labeled thrombus in excised brain, while the microCT technique visualizes thrombus inside living animals using gold-nanoparticles.

Doğrudan Serebral emboli görselleştirme için Kombine Yakın kızılötesi Floresan Görüntüleme ve Mikro bilgisayarlı Tomografi

Direct thrombus imaging visualizes the root cause of thromboembolic infarction. Being able to image thrombus directly allows far better investigation of ...

Induction of Accelerated Atherosclerosis in Mice: The "Wire-Injury" Model

Atherosclerosis is a proliferative fibro-inflammatory disease developing in the arterial wall, inducing a deficient blood flow or a lack of blood flow. Moreover, by rupture of the defective vascular wall, atherosclerosis induces occlusive thrombus formation, which represents the main cause of myocardial infarction or stroke and the most frequent cause of death. Despite the advances in the cardiovascular field, many questions remain unanswered, and additional basic research is essential to improve our understanding of the molecular mechanisms during atherosclerosis and its effects. Due to limited clinical studies, there is a need for representative animal models recreating atherosclerotic conditions such as neointima formation after stent implantation, balloon angioplasty, or endarterectomy. Since the mouse presents many advantages and is the most frequently used model for studying molecular processes, the current study proposes an invasive procedure of endothelial denudation, also known as the wire-injury model, which is representative of the human condition of neointima formation in arteries after revascularization procedures.

Induction of Accelerated Atherosclerosis in Mice: The &quot;Wire-Injury&quot; Model

This study describes an invasive procedure for the induction of accelerated atherosclerosis in mice. In comparison to other methods using electric- or cryo-induced injury, mechanical-induced injury mimics the human condition of restenosis after revascularization therapies and is ideal for the study of the molecular mechanisms involved.

Farelerde Hızlandırılmış Ateroskleroz Indüksiyonu: "Tel-Yaralanma" Modeli

Atherosclerosis is a proliferative fibro-inflammatory disease developing in the arterial wall, inducing a deficient blood flow or a lack of blood flow. ...