Quantification of the Respiratory Burst Response as an Indicator of Innate Immune Health in Zebrafish

The phagocyte respiratory burst is part of the innate immune response to  pathogen infection and involves the production of reactive oxygen species (ROS). ...

Using Zebrafish Models of Human Influenza A Virus Infections to Screen Antiviral Drugs and Characterize Host Immune Cell Responses

Each year, seasonal influenza outbreaks profoundly affect societies worldwide. In spite of global efforts, influenza remains an intractable healthcare ...

University of Maine

Cells and their surrounding extracellular matrix microenvironment interact throughout all stages of life. Understanding the continuously changing scope of cell-matrix interactions in vivo is crucial to garner insights into both congenital birth defects and disease progression. A current challenge in the field of developmental biology is to adapt in vitro tools and rapidly evolving imaging technology to study cell-matrix interactions in a complex 4-D environment. In this review, we highlight the dynamic modulation of cell-matrix interactions during development. We propose that individual cell-matrix adhesion proteins are best considered as complex proteins that can play multiple, often seemingly contradictory roles, depending upon the context of the microenvironment. In addition, cell-matrix proteins can also exert different short versus long term effects. It is thus important to consider cell behavior in light of the microenvironment because of the constant and dynamic reciprocal interactions occurring between them. Finally, we suggest that analysis of cell-matrix interactions at multiple levels (molecules, cells, tissues) in vivo is critical for an integrated understanding because different information can be acquired from all size scales.

Dynamic interactions between cells and their extracellular matrix mediate embryonic development.

Cell-matrix adhesion complexes (CMACs) play fundamental roles during morphogenesis. Given the ubiquitous nature of CMACs and their roles in many cellular processes, one question is how specificity of CMAC function is modulated. The clearly defined cell behaviors that generate segmentally reiterated axial skeletal muscle during zebrafish development comprise an ideal system with which to investigate CMAC function during morphogenesis. We found that Nicotinamide riboside kinase 2b (Nrk2b) cell autonomously modulates the molecular composition of CMACs in vivo. Nrk2b is required for normal Laminin polymerization at the myotendinous junction (MTJ). In Nrk2b-deficient embryos, at MTJ loci where Laminin is not properly polymerized, muscle fibers elongate into adjacent myotomes and are abnormally long. In yeast and human cells, Nrk2 phosphorylates Nicotinamide Riboside and generates NAD+ through an alternative salvage pathway. Exogenous NAD+ treatment rescues MTJ development in Nrk2b-deficient embryos, but not in laminin mutant embryos. Both Nrk2b and Laminin are required for localization of Paxillin, but not beta-Dystroglycan, to CMACs at the MTJ. Overexpression of Paxillin in Nrk2b-deficient embryos is sufficient to rescue MTJ integrity. Taken together, these data show that Nrk2b plays a specific role in modulating subcellular localization of discrete CMAC components that in turn plays roles in musculoskeletal development. Furthermore, these data suggest that Nrk2b-mediated synthesis of NAD+ is functionally upstream of Laminin adhesion and Paxillin subcellular localization during MTJ development. These results indicate a previously unrecognized complexity to CMAC assembly in vivo and also elucidate a novel role for NAD+ during morphogenesis.

Nrk2b-mediated NAD+ production regulates cell adhesion and is required for muscle morphogenesis in vivo: Nrk2b and NAD+ in muscle morphogenesis.

&#x808C;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x662F;&#x5E38;&#x89C1;&#xFF0C;&#x76EE;&#x524D;&#x65E0;&#x6CD5;&#x6CBB;&#x6108;&#x7684;&#x75BE;&#x75C5;&#x3002;&#x4ECE;&#x9057;&#x4F20;&#x4E2D;&#x65AD;&#xFF0C;&#x5C06;&#x808C;&#x8089;&#x7EA4;&#x7EF4;&#x9644;&#x52A0;&#x5230;&#x5176;&#x5468;&#x56F4;&#x7684;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x5FAE;&#x73AF;&#x5883;&#x7684;&#x914D;&#x5408;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x7ED3;&#x679C;&#x7684;&#x5B50;&#x96C6;&#x3002;&#x7EC6;&#x80DE;&#x57FA;&#x8D28;&#x7C98;&#x8FDE;&#x662F;&#x7CBE;&#x81F4;&#x4F20;&#x611F;&#x5668;&#x7684;&#x751F;&#x7406;&#x6761;&#x4EF6;&#x548C;&#x8C03;&#x89E3;&#x54CD;&#x5E94;&#x7684;&#x5141;&#x8BB8;&#x5355;&#x5143;&#x683C;&#xFF0C;&#x4EE5;&#x9002;&#x5E94;&#x4E0D;&#x65AD;&#x53D8;&#x5316;&#x7684;&#x6761;&#x4EF6;&#x3002;&#x56E0;&#x6B64;&#xFF0C;&#x4E89;&#x53D6;&#x4E3A;&#x672A;&#x6765;&#x6CBB;&#x7597;&#x5E94;&#x7528;&#x7A0B;&#x5E8F;&#x627E;&#x5230;&#x76EE;&#x6807;&#x7684;&#x4E00;&#x79CD;&#x529E;&#x6CD5;&#x662F;&#x786E;&#x5B9A;&#x8C03;&#x89E3;&#x8FD9;&#x4E9B;&#x52A8;&#x6001;&#x7684;&#x3001; &#x81EA;&#x9002;&#x5E94;&#x7684;&#x53CD;&#x5E94;&#xFF0C;&#x4F53;&#x5185;&#x7684;&#x7EC6;&#x80DE;&#x7C98;&#x9644;&#x901A;&#x8DEF;&#x3002;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#x8FD9;&#x70DF;&#x9170;&#x80FA;&#x6838;&#x82F7;&#x6FC0;&#x9176;&#x4ECB;&#x5BFC; 2b NAD + &#x5408;&#x6210;&#xFF0C;&#x5176;&#x529F;&#x80FD;&#x662F;&#x5C0F;&#x5206;&#x5B50;&#x6FC0;&#x52A8;&#x5242;&#x808C;&#x8089;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x7C98;&#x9644;&#xFF0C;&#x7EA0;&#x6B63;&#x4E86;&#x6591;&#x9A6C;&#x9C7C;&#x7F3A;&#x4E4F;&#x6297;&#x808C;&#x840E;&#x7F29;&#x86CB;&#x767D;&#x7CD6;&#x86CB;&#x767D;&#x590D;&#x5408;&#x4F53;&#x7684;&#x4E3B;&#x8981;&#x7EC4;&#x4EF6;&#x6216;&#x6574;&#x5408;&#x7D20; alpha7 &#x8425;&#x517B;&#x4E0D;&#x826F;&#x6027;&#x578B;&#x3002;&#x5916;&#x6E90; NAD + &#x6216;&#x5230; NAD + &#x7EF4;&#x751F;&#x7D20;&#x524D;&#x4F53;&#x51CF;&#x5C11;&#x808C;&#x8089;&#x7EA4;&#x7EF4;&#x53D8;&#x6027;&#x548C;&#x6210;&#x679C;&#x660E;&#x663E;&#x66F4;&#x5FEB;&#x9003;&#x51FA;&#x7B54;&#x590D;&#x4E2D;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x7684;&#x80DA;&#x80CE;&#x3002;&#x6869;&#x86CB;&#x767D;&#xFF0C;&#x7EC6;&#x80DE;&#x7C98;&#x9644;&#x86CB;&#x767D;&#x4E0B;&#x6E38;&#x7684; NAD + &#x8FD9;&#x79CD;&#x65B0;&#x578B;&#x7EC6;&#x80DE;&#x7C98;&#x9644;&#x901A;&#x8DEF;&#x4E2D;&#x7684;&#x9AD8;&#x6548;&#x8868;&#x8FBE;&#x964D;&#x4F4E;&#x4E86;&#x5B8C;&#x6574;&#x6574;&#x5408;&#x7D20;&#x53D7;&#x4F53;&#x4E0E;&#x6591;&#x9A6C;&#x9C7C;&#x808C;&#x8089;&#x9000;&#x5316;&#xFF0C;&#x4F46;&#x5E76;&#x4E0D;&#x80FD;&#x63D0;&#x9AD8;&#x52A8;&#x529B;&#x3002;&#x6B64;&#x901A;&#x8DEF;&#x7684;&#x6FC0;&#x6D3B;&#x4F1A;&#x5927;&#x5927;&#x589E;&#x52A0;&#x7EC4;&#x7EC7;&#x5C42;&#x7C98;&#x8FDE;&#x86CB;&#x767D;&#x3001; &#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x57FA;&#x5E95;&#x819C;&#x7684;&#x4E3B;&#x8981;&#x7EC4;&#x6210;&#x90E8;&#x5206;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7ED3;&#x679C;&#x663E;&#x793A;&#x7684;&#x4E3B;&#x8981;&#x4FDD;&#x62A4;&#x4F5C;&#x7528; NAD + &#x4ECE;&#x53D8;&#x5316;&#x5BFC;&#x81F4;&#x57FA;&#x5E95;&#x819C;&#xFF0C;&#x91CE;&#x751F;&#x578B;&#x57FA;&#x5E95;&#x819C;&#x662F;&#x4E0D;&#x8DB3;&#x4EE5;&#x589E;&#x52A0;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x6027;&#x7684;&#x808C;&#x8089;&#x7EA4;&#x7EF4;&#x635F;&#x574F;&#x7684;&#x6297;&#x707E;&#x80FD;&#x529B;&#x3002;NAD + &#x8865;&#x5145;&#x6539;&#x5584;&#x6297;&#x808C;&#x840E;&#x7F29;&#x86CB;&#x767D;&#x7CD6;&#x86CB;&#x767D;&#x590D;&#x5408;&#x7269;&#x6216;&#x6574;&#x5408;&#x7D20; alpha7 &#x7F3A;&#x6591;&#x9A6C;&#x9C7C;&#x7684;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x7684;&#x4EBA;&#x60CA;&#x8BB6;&#x7684;&#x7ED3;&#x679C;&#x8868;&#x660E;&#x5B58;&#x5728;&#x7684;&#x9644;&#x52A0;&#x5C42;&#x7C98;&#x8FDE;&#x86CB;&#x767D;&#x4F53;&#x590D;&#x6742;&#x951A;&#x5B9A;&#x5230;&#x5730;&#x4E0B;&#x5BA4;&#x819C;&#x7684;&#x808C;&#x8089;&#x7EA4;&#x7EF4;&#x3002;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#x6574;&#x5408;&#x7D20; alpha6 &#x53C2;&#x52A0;&#x8FD9;&#x4E2A;&#x9014;&#x5F84;&#xFF0C;&#x4F46;&#x6574;&#x5408;&#x7D20; alpha7 &#x6216;&#x6297;&#x808C;&#x840E;&#x7F29;&#x86CB;&#x767D;&#x7CD6;&#x86CB;&#x767D;&#x590D;&#x5408;&#x7269;&#x9700;&#x8981;&#x6574;&#x5408;&#x7D20; alpha6 &#x7ED3;&#x5408;&#xFF0C;&#x4EE5;&#x51CF;&#x5C11;&#x808C;&#x8089;&#x53D8;&#x6027;&#x3002;&#x4E24;&#x8005;&#x5408;&#x8BA1;&#xFF0C;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x5B9A;&#x4E49;&#x53EF;&#x80FD;&#x6709;&#x672A;&#x6765;&#x7684;&#x6CBB;&#x7597;&#x610F;&#x4E49;&#xFF0C;&#x4E3A;&#x5E7F;&#x6CDB;&#x7684;&#x808C;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x7684;&#x65B0;&#x578B;&#x7EC6;&#x80DE;&#x7C98;&#x9644;&#x901A;&#x8DEF;&#x3002;

NAD + &#x751F;&#x7269;&#x5408;&#x6210;&#x6539;&#x5584;&#x808C;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x75C7;&#x7684;&#x6591;&#x9A6C;&#x9C7C;&#x6A21;&#x578B;&#x3002;

Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha6 to reduce muscle degeneration. Taken together, these results define a novel cell adhesion pathway that may have future therapeutic relevance for a broad spectrum of muscular dystrophies.

NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.

Les dystrophies musculaires sont des maladies communes, actuellement incurables. Un sous-ensemble des dystrophies r&eacute;sultent de perturbations g&eacute;n&eacute;tiques complexes qui s&#39;attachent les fibres musculaires de leur microenvironnement de la matrice extracellulaire environnante. Les adh&eacute;rences cellule-matrice sont exquis capteurs des conditions physiologiques et m&eacute;diates des r&eacute;ponses qui permettent aux cellules de s&#39;adapter aux conditions changeantes. Ainsi, une approche visant &agrave; trouver des cibles pour de futures applications th&eacute;rapeutiques consiste &agrave; identifier les voies d&#39;adh&eacute;rence cellulaire qui v&eacute;hiculent ces r&eacute;ponses dynamiques, adaptatifs, in vivo. Nous trouvons que nicotinamide riboside kinase induite par 2 b la NAD + biosynth&egrave;se, qui fonctionne comme un agoniste de petites mol&eacute;cules d&#39;adh&eacute;rence de la matrice extracellulaire-fibres musculaires, corrige les ph&eacute;notypes dystrophiques chez le poisson z&egrave;bre manque un composant principal du complexe dystrophine-glycoprot&eacute;ine ou l&#39;int&eacute;grine alpha7. Exog&egrave;ne NAD + ou un pr&eacute;curseur de la vitamine &agrave; NAD + r&eacute;duit la d&eacute;g&eacute;n&eacute;rescence des fibres musculaires et entra&icirc;ne des r&eacute;ponses &eacute;vasion nettement plus rapides dans les embryons dystrophiques. La surexpression de la paxillin, une adh&eacute;rence prot&eacute;ine cellulaire en aval du NAD + dans cette voie d&#39;adh&eacute;rence cellulaire roman, r&eacute;duit la d&eacute;g&eacute;n&eacute;rescence musculaire chez le poisson z&egrave;bre avec les int&eacute;grines intact mais n&#39;am&eacute;liore pas la motilit&eacute;. L&#39;activation de cette voie augmente consid&eacute;rablement l&#39;organisation de la laminine, une composante majeure de la membrane basale de la matrice extracellulaire. Nos r&eacute;sultats indiquent que les principaux effets protecteurs de NAD + r&eacute;sultent de modifications de la membrane basale, puisqu&#39;une membrane de sous-sol de type sauvage est suffisante pour accro&icirc;tre la r&eacute;silience des fibres du muscle dystrophiques d&#39;endommager. Le r&eacute;sultat surprenant que NAD + suppl&eacute;mentation am&eacute;liore la dystrophie de la dystrophine-glycoprot&eacute;ine complexe - ou int&eacute;grine alpha7-deficient zebrafish sugg&egrave;re l&#39;existence d&#39;une complexe de r&eacute;cepteur laminine suppl&eacute;mentaires qui ancre les fibres musculaires &agrave; la membrane basale. Nous constatons que l&#39;int&eacute;grine alpha6 participe &agrave; cette voie, mais int&eacute;grine alpha7 ou le complexe de la dystrophine-glycoprot&eacute;ine est tenu en conjonction avec l&#39;int&eacute;grine alpha6 de r&eacute;duire la d&eacute;g&eacute;n&eacute;rescence musculaire. Pris ensemble, ces r&eacute;sultats d&eacute;finissent une voie d&#39;adh&eacute;rence cellulaire roman qui peut avoir une pertinence th&eacute;rapeutique future pour un large spectre des dystrophies musculaires.

NAD + biosynth&egrave;se am&eacute;liore un mod&egrave;le zebrafish de dystrophie musculaire.

Muskeldystrophien sind die &uuml;blichen, derzeit unheilbare Krankheiten. Eine Teilmenge der Dystrophien ergeben sich aus genetischen St&ouml;rungen in komplexen, die Muskelfasern ihrer umgebenden extrazellul&auml;ren Matrix Mikromilieu beimessen. Zelle-Matrix Adh&auml;sionen sind exquisite Sensoren der physiologischen Bedingungen und vermitteln Antworten, die Zellen zur Anpassung an ver&auml;nderte Bedingungen zu erm&ouml;glichen. So ist ein Ansatz zur Suche nach Zielen f&uuml;r zuk&uuml;nftige therapeutische Anwendungen Zelle Adh&auml;sion Wege zu identifizieren, die diese dynamischen, adaptiven Reaktionen, die in-vivo zu vermitteln. Wir finden, dass Nicotinamid Riboside Kinase 2b-vermittelte NAD + Biosynthese, welche Funktionen als ein kleines Molek&uuml;l-Agonist der Muskelfaser-extrazellul&auml;ren Matrix Haftung, korrigiert dystrophische Ph&auml;notypen im Zebrafisch fehlt eine Hauptkomponente des Dystrophin-Glykoprotein Komplexes oder Integrin alpha7. Exogene NAD + oder eine Vitamin-Vorstufe zu NAD + reduziert Muskelfaser Entartung und f&uuml;hrt zu deutlich schneller Flucht Antworten dystrophische Embryonen. Eine &Uuml;berexpression von Paxillin, ein Zelle Adh&auml;sion Protein stromabw&auml;rts von NAD + in diesem neuartigen Zelle Adh&auml;sion Weg, Muskel-Degeneration im Zebrafish mit intakten Integrin-Rezeptoren reduziert aber nicht Motilit&auml;t verbessert. Aktivierung des dieses Signalweges Goldangebots Organisation von Laminin, ein wesentlicher Bestandteil der extrazellul&auml;ren Matrix-Basalmembran. Unsere Ergebnisse zeigen, dass die prim&auml;re sch&uuml;tzende Wirkung von NAD + aus Ver&auml;nderungen der Basalmembran ergeben, wie ein Wildtyp-Basalmembran ausreicht, um die Widerstandsf&auml;higkeit der dystrophische Muskelfasern zu besch&auml;digen zu erh&ouml;hen. &Uuml;berraschende Ergebnis, dass NAD + Supplementierung Dystrophie im Dystrophin-Glykoprotein komplex oder Integrin alpha7-defizienten Zebrafisch aerztlichen schl&auml;gt das Vorhandensein einer zus&auml;tzlichen Laminin Rezeptor-Komplexe, die Muskelfasern an der Basalmembran verankert. Wir finden, dass Integrin alpha6 beteiligt sich an diesem Weg, aber entweder Integrin alpha7 oder der Dystrophin-Glykoprotein-Komplex in Verbindung mit Integrin alpha6 ben&ouml;tigt wird, um Muskel-Degeneration zu reduzieren. Zusammengenommen definieren diese Ergebnisse einen neuartigen Zelle Adh&auml;sion Weg, der zuk&uuml;nftige therapeutische Relevanz f&uuml;r ein breites Spektrum von Muskeldystrophien haben k&ouml;nnten.

NAD + Biosynthese aerztlichen ein Zebrafisch-Modell der Muskeldystrophie.

Le distrofie muscolari sono malattie comuni, attualmente incurabili. Un sottoinsieme delle distrofie risultato dalla genetiche interruzioni nei complessi che si attaccano le fibre muscolari a loro microambiente extracellulare circostante. Adesioni cellula-matrice sono squisiti sensori di condizioni fisiologiche e mediare le risposte che permettono alle cellule di adattarsi alle mutevoli condizioni. Cos&igrave;, un approccio verso l&#39;individuazione di obiettivi per applicazioni terapeutiche future &egrave; quello di individuare percorsi di adesione delle cellule che mediano queste risposte dinamiche, adaptive in vivo. Troviamo quello nicotinamide riboside chinasi mediata 2b NAD + biosintesi, che funziona come un agonista di piccola molecola di adesione della matrice extracellulare della fibra muscolare, corregge distrofici fenotipi in zebrafish manca una componente primaria del complesso distrofina-glicoproteina o integrina alpha7. Esogeno NAD + o un precursore della vitamina a NAD + riduce la degenerazione della fibra muscolare e si traduce in risposte di fuga significativamente pi&ugrave; veloce negli embrioni distrofiche. Sovraespressione di paxillin, una cellula adesione proteina a valle di NAD + in questo percorso di adesione cellula romanzo, riduce la degenerazione muscolare nello zebrafish con recettori integrin intatto ma non migliora la motilit&agrave;. Attivazione di questo pathway aumenta significativamente l&#39;organizzazione di laminina, un importante componente della membrana basale extracellulare. I nostri risultati indicano che gli effetti protettivi primari del NAD + derivano da modifiche alla membrana basale, come una membrana basale del selvaggio-tipo &egrave; sufficiente per aumentare la resistenza delle fibre muscolari distrofiche ai danni. Il risultato sorprendente che NAD + supplementazione migliora distrofia in dystrophin glycoprotein complex - o integrina alpha7-carenti zebrafish suggerisce l&#39;esistenza di un complesso recettoriale laminina supplementari che ancore la membrana basale delle fibre muscolari. Troviamo che integrin alpha6 partecipa a questo percorso, ma in combinazione con integrin alpha6 per ridurre la degenerazione muscolare &egrave; necessaria integrina alpha7 o il complesso distrofina-glicoproteina. Presi insieme, questi risultati definiscono un percorso di adesione cellula romanzo che possa avere rilevanza terapeutica futura per un ampio spettro di distrofie muscolari.

NAD + biosintesi migliora un modello zebrafish di distrofia muscolare.

&#x7B4B;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x306F;&#x3001;&#x4E00;&#x822C;&#x7684;&#x306A;&#x73FE;&#x5728;&#x4E0D;&#x6CBB;&#x306E;&#x75C5;&#x6C17;&#x3067;&#x3059;&#x3002;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x7D50;&#x679C;&#x7B4B;&#x7DDA;&#x7DAD;&#x306F;&#x305D;&#x306E;&#x5468;&#x56F2;&#x306E;&#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x306E;&#x5FAE;&#x5C0F;&#x74B0;&#x5883;&#x306B;&#x30A2;&#x30BF;&#x30C3;&#x30C1;&#x932F;&#x4F53;&#x306E;&#x907A;&#x4F1D;&#x7684;&#x6DF7;&#x4E71;&#x304B;&#x3089;&#x306E;&#x30B5;&#x30D6;&#x30BB;&#x30C3;&#x30C8;&#x3067;&#x3059;&#x3002;&#x30BB;&#x30EB; &#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x7652;&#x7740;&#x7D76;&#x5999;&#x306A;&#x30BB;&#x30F3;&#x30B5;&#x30FC;&#x306E;&#x751F;&#x7406;&#x7684;&#x6761;&#x4EF6;&#x3068;&#x7D30;&#x80DE;&#x306E;&#x6761;&#x4EF6;&#x306E;&#x5909;&#x5316;&#x306B;&#x9069;&#x5FDC;&#x3059;&#x308B;&#x4EF2;&#x4ECB;&#x3059;&#x308B;&#x5FDC;&#x7B54;&#x3067;&#x3059;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x5C06;&#x6765;&#x306E;&#x6CBB;&#x7642;&#x30A2;&#x30D7;&#x30EA;&#x30B1;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3092;&#x898B;&#x3064;&#x3051;&#x308B;&#x306B;&#x5411;&#x3051;&#x3066; 1 &#x3064;&#x306E;&#x30A2;&#x30D7;&#x30ED;&#x30FC;&#x30C1;&#x306F;&#x3053;&#x308C;&#x3089;&#x306E;&#x52D5;&#x7684;&#x306A;&#x9069;&#x5FDC;&#x306E;&#x5FDC;&#x7B54;&#x304C; in vivo &#x3067;&#x4EF2;&#x4ECB;&#x3059;&#x308B;&#x7D30;&#x80DE;&#x63A5;&#x7740;&#x7D4C;&#x8DEF;&#x3092;&#x8B58;&#x5225;&#x3057;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005; &#x306F;&#x3001;&#x3069;&#x306E;&#x95A2;&#x6570;&#x3068;&#x3057;&#x3066;&#x4F4E;&#x5206;&#x5B50;&#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x306E;&#x7B4B;&#x7DDA;&#x7DAD;&#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x306E;&#x63A5;&#x7740;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30F3;&#x7CD6;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x8907;&#x5408;&#x4F53;&#x306E;&#x4E3B;&#x8981;&#x306A;&#x30B3;&#x30F3;&#x30DD;&#x30FC;&#x30CD;&#x30F3;&#x30C8;&#x307E;&#x305F;&#x306F;&#x30A4;&#x30F3;&#x30C6;&#x30B0;&#x30EA;&#x30F3; alpha7 &#x6B20;&#x3051;&#x3066;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5; &#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x306E;&#x8868;&#x73FE;&#x578B;&#x3092;&#x4FEE;&#x6B63;&#x3057;&#x307E;&#x3059;&#x305D;&#x306E;&#x30CB;&#x30B3;&#x30C1;&#x30F3;&#x30A2;&#x30DF;&#x30C9; riboside &#x30AD;&#x30CA;&#x30FC;&#x30BC; 2b &#x3092;&#x4ECB;&#x3057;&#x305F; NAD + &#x5408;&#x6210;&#x3001;&#x898B;&#x3064;&#x3051;&#x307E;&#x3059;&#x3002;&#x5916;&#x56E0;&#x6027; NAD + &#x307E;&#x305F;&#x306F;&#x30D3;&#x30BF;&#x30DF;&#x30F3;&#x306E;&#x524D;&#x99C6;&#x4F53;&#x306B; NAD + &#x7B4B;&#x7DDA;&#x7DAD;&#x306E;&#x5909;&#x6027;&#x3092;&#x4F4E;&#x6E1B;&#x3057;&#x3001;&#x5927;&#x5E45;&#x306B;&#x9AD8;&#x901F;&#x306E;&#x30A8;&#x30B9;&#x30B1;&#x30FC;&#x30D7;&#x5FDC;&#x7B54;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x80DA;&#x306B;&#x304A;&#x3051;&#x308B;&#x7D50;&#x679C;&#x3057;&#x307E;&#x3059;&#x3002;Paxillin &#x306E;&#x7D30;&#x80DE;&#x63A5;&#x7740;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x4E0B;&#x6D41;&#x306E; NAD &#xFF0B; &#x3067;&#x3053;&#x306E;&#x65B0;&#x898F;&#x7D30;&#x80DE;&#x63A5;&#x7740;&#x7D4C;&#x8DEF;&#x306E;&#x904E;&#x5270;&#x767A;&#x73FE;&#x306F;&#x3001;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x3092;&#x305D;&#x306E;&#x307E;&#x307E;&#x30A4;&#x30F3;&#x30C6;&#x30B0;&#x30EA;&#x30F3; &#x30EC;&#x30BB;&#x30D7;&#x30BF;&#x30FC;&#x306B;&#x304A;&#x3051;&#x308B;&#x7B4B;&#x5909;&#x6027;&#x3092;&#x4F4E;&#x6E1B;&#x304C;&#x904B;&#x52D5;&#x6027;&#x306F;&#x5411;&#x4E0A;&#x3057;&#x307E;&#x305B;&#x3093;&#x3002;&#x3053;&#x306E;&#x7D4C;&#x8DEF;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;&#x5927;&#x5E45;&#x306B;&#x7D44;&#x7E54;&#x30E9;&#x30DF;&#x30CB;&#x30F3;, &#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x306E;&#x57FA;&#x5E95;&#x819C;&#x306E;&#x4E3B;&#x8981;&#x6210;&#x5206;&#x304C;&#x5897;&#x52A0;&#x3057;&#x307E;&#x3059;&#x3002;&#x91CE;&#x751F;&#x578B;&#x57FA;&#x5E95;&#x819C;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x7B4B;&#x7DDA;&#x7DAD;&#x640D;&#x50B7;&#x3078;&#x306E;&#x56DE;&#x5FA9;&#x529B;&#x3092;&#x5897;&#x52A0;&#x3059;&#x308B;&#x306E;&#x306B;&#x5341;&#x5206;&#x3067;&#x3042;&#x308B;&#x3068;&#x6211;&#x3005; &#x306E;&#x7D50;&#x679C;&#x306E; NAD + &#x30D7;&#x30E9;&#x30A4;&#x30DE;&#x30EA;&#x4FDD;&#x8B77;&#x52B9;&#x679C;&#x304B;&#x3089;&#x5909;&#x66F4;&#x57FA;&#x5E95;&#x819C;&#x306B;&#x751F;&#x3058;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;NAD + &#x88DC;&#x5145;&#x306E;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC; &#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30F3;&#x7CD6;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x8907;&#x5408;&#x4F53;&#x307E;&#x305F;&#x306F;&#x30A4;&#x30F3;&#x30C6;&#x30B0;&#x30EA;&#x30F3; alpha7 &#x6B20;&#x4E4F;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x306E;&#x6539;&#x5584;&#x3082;&#x610F;&#x5916;&#x306A;&#x7D50;&#x679C;&#x306E;&#x7B4B;&#x7DDA;&#x7DAD;&#x57FA;&#x5E95;&#x819C;&#x306B;&#x30A2;&#x30F3;&#x30AB;&#x30FC;&#x3092;&#x8FFD;&#x52A0;&#x30E9;&#x30DF;&#x30CB;&#x30F3;&#x306E;&#x53D7;&#x5BB9;&#x8907;&#x96D1;&#x306A;&#x5B58;&#x5728;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005; &#x306F;&#x3053;&#x306E;&#x7D4C;&#x8DEF;&#x3067;&#x30A4;&#x30F3;&#x30C6;&#x30B0;&#x30EA;&#x30F3; alpha6 &#x53C2;&#x52A0;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x304C;&#x3001;&#x30A4;&#x30F3;&#x30C6;&#x30B0;&#x30EA;&#x30F3; alpha7 &#x307E;&#x305F;&#x306F;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30F3;&#x7CD6;&#x86CB;&#x767D;&#x8CEA;&#x8907;&#x5408;&#x4F53; alpha6 &#x30A4;&#x30F3;&#x30C6;&#x30B0;&#x30EA;&#x30F3;&#x3068;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x3066;&#x7B4B;&#x5909;&#x6027;&#x3092;&#x6E1B;&#x3089;&#x3059;&#x305F;&#x3081;&#x306B;&#x5FC5;&#x8981;&#x3067;&#x3059;&#x898B;&#x3064;&#x3051;&#x307E;&#x3059;&#x3002;&#x4E00;&#x7DD2;&#x306B;&#x53D6;&#x3089;&#x308C;&#x3066;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;&#x5C06;&#x6765;&#x306E;&#x6CBB;&#x7642;&#x95A2;&#x9023;&#x6027;&#x7B4B;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x306E;&#x5E83;&#x3044;&#x30B9;&#x30DA;&#x30AF;&#x30C8;&#x30EB;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x65B0;&#x898F;&#x7D30;&#x80DE;&#x63A5;&#x7740;&#x7D4C;&#x8DEF;&#x3092;&#x5B9A;&#x7FA9;&#x3057;&#x307E;&#x3059;&#x3002;

NAD + &#x751F;&#x5408;&#x6210;&#x306F;&#x7B4B;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x306E;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5; &#x30E2;&#x30C7;&#x30EB;&#x3092;&#x6539;&#x5584;&#x3057;&#x307E;&#x3059;&#x3002;

&#xADFC; &#xC601;&#xC591;&#xC740; &#xC77C;&#xBC18;&#xC801;&#xC73C;&#xB85C;, &#xD604;&#xC7AC; &#xBD88; &#xCE58;&#xC758; &#xC9C8;&#xBCD1;. &#xADFC;&#xC721; &#xC12C;&#xC720; &#xB4E4;&#xC740; &#xC8FC;&#xBCC0; &#xC138;&#xD3EC; &#xC678; &#xAE30;&#xC9C8; microenvironment&#xC5D0; &#xC5F0;&#xACB0; &#xD558;&#xB294; &#xB2E8;&#xC9C0; &#xC720;&#xC804; &#xC911;&#xB2E8;&#xC5D0;&#xC11C; &#xC601;&#xC591; &#xACB0;&#xACFC;&#xC758; &#xD558;&#xC704; &#xC9D1;&#xD569;&#xC785;&#xB2C8;&#xB2E4;. &#xC138;&#xD3EC;-&#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4; &#xC720;&#xCC29;&#xC740; &#xC0DD;&#xB9AC; &#xC801; &#xC870;&#xAC74; &#xBC0F; &#xC140; &#xC870;&#xAC74; &#xBCC0;&#xD654;&#xC5D0; &#xC801;&#xC751;&#xD560; &#xC218; &#xC788;&#xB3C4;&#xB85D; &#xC911;&#xC7AC; &#xC751;&#xB2F5;&#xC758; &#xC808;&#xBB18; &#xD55C; &#xC13C;&#xC11C; &#xC774;&#xB2E4;. &#xB530;&#xB77C;&#xC11C;, &#xD5A5;&#xD6C4; &#xCE58;&#xB8CC; &#xC751;&#xC6A9; &#xD504;&#xB85C;&#xADF8;&#xB7A8;&#xC5D0; &#xB300; &#xD55C; &#xBAA9;&#xD45C;&#xB97C; &#xCC3E;&#xB294; &#xCABD;&#xC73C;&#xB85C; &#xD55C; &#xAC00;&#xC9C0; &#xBC29;&#xBC95;&#xC740; &#xC774;&#xB7EC;&#xD55C; &#xB3D9;&#xC801;, &#xC801;&#xC751;&#xD615; &#xC751;&#xB2F5; vivo&#xC5D0;&#xC11C; &#xC911;&#xC7AC; &#xD558;&#xB294; &#xC138;&#xD3EC; &#xC811;&#xCC29; &#xACBD;&#xB85C; &#xC2DD;&#xBCC4; &#xD558;&#xB294; &#xAC83;. &#xC0DD; &#xADF8; &#xB2C8;&#xCF54;&#xD2F4;&#xC544;&#xBBF8;&#xB4DC; riboside &#xB2C8; 2b &#xC911;&#xC7AC; NAD + &#xD569;&#xC131;, &#xADFC;&#xC721; &#xC12C;&#xC720; &#xC138;&#xD3EC; &#xC678; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4; &#xC811;&#xCC29;&#xC758; &#xC791;&#xC740; &#xBD84;&#xC790; &#xAE38; &#xD56D; &#xC81C;&#xB294; &#xAE30;&#xB2A5; &#xC218;&#xC815; zebrafish dystrophin &#xB2F9;&#xB2E8;&#xBC31;&#xC9C8; &#xBCF5;&#xC7A1; &#xD55C;&#xC758; &#xC8FC;&#xC694; &#xAD6C;&#xC131; &#xC694;&#xC18C; &#xB610;&#xB294; integrin alpha7 &#xBD80;&#xC871; dystrophic &#xACE0;&#xAE30;&#xB97C; &#xCC3E;&#xC744; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. Exogenous NAD + &#xB610;&#xB294; NAD + &#xBE44;&#xD0C0;&#xBBFC; &#xC804;&#xC870; &#xADFC;&#xC721; &#xC12C;&#xC720; &#xBCC0;&#xC131; &#xC904;&#xC5B4;&#xB4E4;&#xACE0; dystrophic &#xBC30;&#xC544;&#xC5D0; &#xD06C;&#xAC8C; &#xD0C8;&#xCD9C; &#xC751;&#xB2F5; &#xACB0;&#xACFC;. Overexpression&#xC758; paxillin, &#xC138;&#xD3EC; &#xC811;&#xCC29; &#xB2E8;&#xBC31;&#xC9C8; &#xD558;&#xB958; NAD +&#xC758;&#xC774; &#xC18C;&#xC124;&#xC740; &#xC138;&#xD3EC; &#xC811;&#xCC29; &#xD1B5;&#xB85C;&#xC5D0;&#xC11C; &#xADF8;&#xB300;&#xB85C; integrin &#xC218;&#xC6A9; &#xCCB4;&#xC640; zebrafish&#xC758; &#xADFC;&#xC721; &#xBCC0;&#xC131; &#xC904;&#xC5B4;&#xB4E4;&#xC9C0;&#xB9CC; &#xC6B4;&#xB3D9; &#xC131; &#xD5A5;&#xC0C1; &#xB418;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774; &#xD1B5;&#xB85C;&#xC758; &#xD65C;&#xC131;&#xD654;&#xB294; &#xD06C;&#xAC8C; laminin, &#xC138;&#xD3EC; &#xC678; &#xAE30;&#xC9C8; &#xC9C0; &#xB9C9;&#xC758; &#xC8FC;&#xC694; &#xAD6C;&#xC131; &#xC694;&#xC18C; &#xC870;&#xC9C1; &#xC99D;&#xAC00;. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xC9C0;&#xD558;&#xC2E4; &#xB9C9;&#xC774; &#xC190;&#xC0C1; dystrophic &#xADFC;&#xC721; &#xC12C;&#xC720;&#xC758; &#xD0C4;&#xB825;&#xC131;&#xC744; &#xB192;&#xC774;&#xAE30; &#xC704;&#xD574; &#xCDA9;&#xBD84; &#xD55C; &#xC0AC;&#xB824;&#xACE0; &#xD588;&#xB358; NAD +&#xC758; &#xAE30;&#xBCF8; &#xBCF4;&#xD638; &#xD6A8;&#xACFC; &#xC9C0;&#xD558;&#xC2E4; &#xB9C9; &#xBCC0;&#xD654;&#xC5D0;&#xC11C; &#xACB0;&#xACFC; &#xB098;&#xD0C0;&#xB0C5;&#xB2C8;&#xB2E4;. &#xC0AC;&#xB824;&#xACE0; &#xD588;&#xB358; NAD + &#xBCF4;&#xCDA9; dystrophin &#xB2F9;&#xB2E8;&#xBC31;&#xC9C8; &#xBCF5;&#xD569; &#xB610;&#xB294; integrin alpha7 &#xBD88;&#xCDA9;&#xBD84; &#xD55C; zebrafish&#xC758; &#xC601;&#xC591; &#xC7A5;&#xC560; ameliorates &#xB180;&#xB77C;&#xC6B4; &#xACB0;&#xACFC; &#xC218;&#xC6A9; &#xB41C; &#xCD94;&#xAC00; laminin &#xCCB4; &#xBCF5;&#xC7A1; &#xD55C; &#xADF8; &#xC9C0;&#xD558;&#xC2E4; &#xB9C9; &#xADFC;&#xC721; &#xC12C;&#xC720; &#xC575;&#xCEE4;&#xC758; &#xC874;&#xC7AC;&#xB97C; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; integrin alpha6&#xC774;&#xC774; &#xD1B5;&#xB85C;&#xC5D0; &#xCC38;&#xC5EC; &#xD558;&#xC9C0;&#xB9CC; integrin alpha7 &#xB610;&#xB294; dystrophin &#xB2F9;&#xB2E8;&#xBC31;&#xC9C8; &#xBCF5;&#xD569; integrin alpha6&#xC640; &#xD568;&#xAED8;&#xC5D0;&#xC11C; &#xADFC;&#xC721; &#xBCC0;&#xC131;&#xC744; &#xC904;&#xC774;&#xAE30; &#xC704;&#xD574; &#xD544;&#xC694;&#xD55C; &#xCC3E;&#xC744;. &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xADFC; &#xC601;&#xC591;&#xC758; &#xAD11;&#xBC94;&#xC704; &#xD55C; &#xC2A4;&#xD399;&#xD2B8;&#xB7FC;&#xC5D0; &#xB300; &#xD55C; &#xBBF8;&#xB798;&#xC758; &#xCE58;&#xB8CC; &#xC801; &#xAD00;&#xB828;&#xC131;&#xC744; &#xAC00;&#xC9C8; &#xC218; &#xC788;&#xB294; &#xC0C8;&#xB85C;&#xC6B4; &#xC138;&#xD3EC; &#xC811;&#xCC29; &#xACBD;&#xB85C; &#xC815;&#xC758; &#xD568;&#xAED8; &#xCC0D;&#xC740;.

&#xC0AC;&#xB824;&#xACE0; &#xD588;&#xB358; NAD + &#xC0DD; &#xD569;&#xC131; &#xADFC; &#xC704;&#xCD95; &#xC99D;&#xC758; zebrafish &#xBAA8;&#xB378; ameliorates.

Distrofias musculares son enfermedades comunes, actualmente incurables. Un subconjunto de distrofias resultado de alteraciones gen&eacute;ticas en complejos que se adhieren las fibras musculares a su microambiente circundante de la matriz extracelular. Adherencias c&eacute;lula-matriz son exquisitos sensores de condiciones fisiol&oacute;gicas y mediatos las respuestas que permiten a las c&eacute;lulas a adaptarse a las condiciones cambiantes. Por lo tanto, un enfoque hacia la b&uacute;squeda de objetivos para futuras aplicaciones terap&eacute;uticas es identificar v&iacute;as de adhesi&oacute;n celular que median estas respuestas din&aacute;micas y capacidad de adaptaci&oacute;n en vivo. Encontramos nicotinamida dos quinasa 2b-mediada NAD + bios&iacute;ntesis, que funciona como un agonista de la peque&ntilde;a mol&eacute;cula de adherencia de la matriz extracelular de la fibra del m&uacute;sculo, corrige distr&oacute;ficos fenotipos en pez cebra que falta un componente principal del complejo distrofina-glucoprote&iacute;na o integrina alpha7. Ex&oacute;geno NAD + o un precursor de la vitamina a NAD + reduce la degeneraci&oacute;n de la fibra del m&uacute;sculo y da lugar a respuestas de escape significativamente m&aacute;s r&aacute;pidas en embriones distr&oacute;ficos. Sobreexpresi&oacute;n de paxillin, una adherencia prote&iacute;na celular aguas abajo de NAD + en esta v&iacute;a de adhesi&oacute;n celular novela, reduce la degeneraci&oacute;n muscular en pez cebra con receptores de integrina intacto pero no mejora la motilidad. Activaci&oacute;n de esta v&iacute;a aumenta significativamente la organizaci&oacute;n de laminina, un componente importante de la membrana basal de la matriz extracelular. Nuestros resultados indican que los principales efectos protectores de NAD + provocados por cambios de la membrana basal, como una membrana del s&oacute;tano de tipo salvaje es suficiente para incrementar la resistencia de las fibras de m&uacute;sculo distr&oacute;ficas da&ntilde;ar. El resultado sorprendente que NAD + suplementaci&oacute;n mejora distrofia en pez cebra distrofina-glucoprote&iacute;na complejo - o integrina alpha7 deficientes sugiere la existencia de un complejo de receptor de laminina adicional que ancla las fibras musculares a la membrana basal. Encontramos que la integrina alpha6 participa en esta v&iacute;a, pero integrina alpha7 o el complejo distrofina-glucoprote&iacute;na es necesaria junto con la integrina alpha6 para reducir la degeneraci&oacute;n muscular. Tomados en conjunto, estos resultados definen un camino de adhesi&oacute;n celular nuevo que tenga importancia terap&eacute;utica futura para un amplio espectro de distrofias musculares.

Bios&iacute;ntesis de NAD + mejora un modelo de pez cebra de distrofia muscular.

Humans and viruses have a long co-evolutionary history. Viral illnesses have and will continue to shape human history: from smallpox, to influenza, to HIV, and beyond. Animal models of human viral illnesses are needed in order to generate safe and effective antiviral medicines, adjuvant therapies, and vaccines. These animal models must support the replication of human viruses, recapitulate aspects of human viral illnesses, and respond with conserved immune signaling cascades. The zebrafish is perhaps the simplest, most commonly used laboratory model organism in which innate and/or adaptive immunity can be studied. Herein, we will discuss the current zebrafish models of human viral illnesses and the insights they have provided. We will highlight advantages of early life stage zebrafish and the importance of innate immunity in human viral illnesses. We will also discuss viral characteristics to consider before infecting zebrafish with human viruses as well as predict other human viruses that may be able to infect zebrafish.

Studying the immune response to human viral infections using zebrafish.

Seasonal influenza virus infections cause annual epidemics and sporadic pandemics. These present a global health concern, resulting in substantial morbidity, mortality and economic burdens. Prevention and treatment of influenza illness is difficult due to the high mutation rate of the virus, the emergence of new virus strains and increasing antiviral resistance. Animal models of influenza infection are crucial to our gaining a better understanding of the pathogenesis of and host response to influenza infection, and for screening antiviral compounds. However, the current animal models used for influenza research are not amenable to visualization of host-pathogen interactions or high-throughput drug screening. The zebrafish is widely recognized as a valuable model system for infectious disease research and therapeutic drug testing. Here, we describe a zebrafish model for human influenza A virus (IAV) infection and show that zebrafish embryos are susceptible to challenge with both influenza A strains APR8 and X-31 (Aichi). Influenza-infected zebrafish show an increase in viral burden and mortality over time. The expression of innate antiviral genes, the gross pathology and the histopathology in infected zebrafish recapitulate clinical symptoms of influenza infections in humans. This is the first time that zebrafish embryos have been infected with a fluorescent IAV in order to visualize infection in a live vertebrate host, revealing a pattern of vascular endothelial infection. Treatment of infected zebrafish with a known anti-influenza compound, Zanamivir, reduced mortality and the expression of a fluorescent viral gene product, demonstrating the validity of this model to screen for potential antiviral drugs. The zebrafish model system has provided invaluable insights into host-pathogen interactions for a range of infectious diseases. Here, we demonstrate a novel use of this species for IAV research. This model has great potential to advance our understanding of influenza infection and the associated host innate immune response.

Influenza A virus infection in zebrafish recapitulates mammalian infection and sensitivity to anti-influenza drug treatment.

Skeletal muscle specification and morphogenesis during early development are critical for normal physiology. In addition to mediating locomotion, skeletal muscle is a secretory organ that contributes to metabolic homeostasis. Muscle is a highly adaptable tissue, as evidenced by the ability to increase muscle cell size and/or number in response to weight bearing exercise. Conversely, muscle wasting can occur during aging (sarcopenia), cancer (cancer cachexia), extended hospital stays (disuse atrophy), and in many genetic diseases collectively known as the muscular dystrophies and myopathies. It is therefore of great interest to understand the cellular and molecular mechanisms that mediate skeletal muscle development and adaptation. Muscle morphogenesis transforms short muscle precursor cells into long, multinucleate myotubes that anchor to tendons via the myotendinous junction. This process requires carefully orchestrated interactions between cells and their extracellular matrix microenvironment. These interactions are dynamic, allowing muscle cells to sense biophysical, structural, organizational, and/or signaling changes within their microenvironment and respond appropriately. In many musculoskeletal diseases, these cell adhesion interactions are disrupted to such a degree that normal cellular adaptive responses are not sufficient to compensate for accumulating damage. Thus, one major focus of current research is to identify the cell adhesion mechanisms that drive muscle morphogenesis, with the hope that understanding how muscle cell adhesion promotes the intrinsic adaptability of muscle tissue during development may provide insight into potential therapeutic approaches for muscle diseases. Our objectives in this review are to highlight recent studies suggesting conserved roles for cell-extracellular matrix adhesion in vertebrate muscle morphogenesis and cellular adaptive responses in animal models of muscle diseases.

Hanging on for the ride: adhesion to the extracellular matrix mediates cellular responses in skeletal muscle morphogenesis and disease.

Remodeling of the extracellular matrix (ECM) regulates cell adhesion as well as signaling between cells and their microenvironment. Despite the importance of tightly regulated ECM remodeling for normal muscle development and function, mechanisms underlying ECM remodeling in vivo remain elusive. One excellent paradigm in which to study ECM remodeling in vivo is morphogenesis of the myotendinous junction (MTJ) during zebrafish skeletal muscle development. During MTJ development, there are dramatic shifts in the primary components comprising the MTJ matrix. One such shift involves the replacement of Fibronectin (Fn)-rich matrix, which is essential for both somite and early muscle development, with laminin-rich matrix essential for normal function of the myotome. Here, we investigate the mechanism underlying this transition.

Michelle F. Goody

Department of Molecular and Biomedical Sciences,
School of Biology and Ecology

University of Maine

Quantification of the Respiratory Burst Response as an Indicator of Innate Immune Health in Zebrafish

Using Zebrafish Models of Human Influenza A Virus Infections to Screen Antiviral Drugs and Characterize Host Immune Cell Responses

Michelle F. Goody

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Molecular and Biomedical Sciences,School of Biology and Ecology

University of Maine

Quantification of the Respiratory Burst Response as an Indicator of Innate Immune Health in Zebrafish

Using Zebrafish Models of Human Influenza A Virus Infections to Screen Antiviral Drugs and Characterize Host Immune Cell Responses

Department of Molecular and Biomedical Sciences,
School of Biology and Ecology