Cell Adhesion in Cardiovascular Biology and Pathology

这个项目的总体目标是提高我们对细胞黏附受体和 细胞外基质(ECM)蛋白在心血管发育、维持、修复和病理中的作用 小鼠模型和细胞生物学方法，以及越来越多地使用基因组规模的方法。我们的 主要兴趣是心脏发育、血管生成(生理和病理)和 止血/血栓形成。所有这些都涉及细胞黏附事件，我们的目标是提供更深层次的 了解所涉及的分子和细胞机制。这样的认识具有重大的意义 对治疗方法的影响，因为细胞黏附蛋白可以在细胞外获得，并且非常好 针对已知的黏附受体的药物是有先例的，特别是在血栓形成、炎症和 自身免疫性疾病。我们在黏附蛋白的作用方面有长期的合作 炎症和止血/血栓与瓦格纳博士的合作，瓦格纳博士现在是该项目的成员。我们 还与Krieger博士合作，探索血管细胞黏附对模型的贡献 他患上了冠心病。这两项合作将在下一笔赠款中继续 期间，还将纳入在血管生成方面的合作，这一主题一直是 在过去的资助期间，我们自己的研究努力。在下一阶段，我们的合作将继续下去， 更多地关注与人类疾病的联系。我们和罗迪什人有许多共同的兴趣 实验室。并计划在下一个资金期开展更多合作，调查 脂联素、纤维连接蛋白和整合素。 我们的主要目标如下： 1.定位定位于4号染色体5MbP区域的修饰基因(S)(QTL) 在心脏发育过程中与纤维连接蛋白基因相互作用。身份将由苏格兰民族党继续进行 与小鼠HapMap相结合，与表达谱数据交叉相关，并通过 RNA干扰。 2.分析现有菌株(加上我们正在产生的其他菌株)在其 纤维连接蛋白的表达和剪接。这些小鼠将首先接受血管缺陷的调查。 发育和血管生成。 3.此外，还将使用fn缺失的内皮细胞和重组fn进行体外分析。 异构体在细胞生物学水平上测试它们对细胞的影响。 4.我们将继续深入研究各种整合素在血管生成中的作用，尤其是 重点关注在血管系统中作为FN受体的整合素。 5.我们将研究fn及其剪接异构体在止血和血栓形成中的作用。 活体、体外和体外方法继续我们对这个问题的长期兴趣和我们最近的 与瓦格纳博士在这一主题上的合作。 6.我们已经发起并将扩大与克里格博士的合作，将我们在粘合方面的专业知识结合起来 我们的小鼠品系在许多相关的黏附受体和ECM蛋白上与Krieger博士的 在冠心病(CHD)和他的CHD小鼠模型方面的专业知识。

The overall aim of this project is to improve our understanding of the role of cell adhesion receptors and extracellular matrix (ECM) proteins in cardiovascular development, maintenance, repair and pathology, using mouse models and cell biological approaches, as well as increasing use of genome-scale approaches. Our main interests are in heart development, angiogenesis (both physiological and pathological) and hemostasis/thrombosis. All these involve cell adhesion events and our aim is to provide a deeper understanding of the molecular and cellular mechanisms involved. Such an understanding has major implications for therapeutic approaches, since cell adhesion proteins are accessible outside cells and excellent precedents exist for drugs that target known adhesion receptors, especially in thrombosis, inflammation and autoimmune disease. We have had long-standing collaborations on the roles of adhesion proteins in inflammation and hemostasis/thrombosis with Dr. Wagner, who is now a member of this Program Project. We are also collaborating with Dr. Krieger, probing the contributions of adhesion of vascular cells to the models of coronary heart disease that he has developed. Both of those collaborations will continue in the next grant period and will also incorporate collaborations on angiogenesis, a topic which has been a major component of our own research effort during the past funding period. In the next period, our collaborations will continue, with an increased focus on connections to human disease. We have many interests in common with the Lodish lab. and are planning additional collaborations during the next funding period investigating links among adiponectins, fibronectins and integrins. Our main aims will be as follows:- 1. to identify a modifier gene(s) (QTL) that we have mapped to a 5Mbp region on chromosome 4, which interacts with the fibronectin gene during cardiac development. Identification will be by continued SNP mapping combined with the mouse HapMap, cross-correlated with expression profiling data and tested by RNA interference. 2. to analyze existing strains (plus additional ones that we are generating) that are altered in their expression and splicing of fibronectin. Those mice will be investigated first for defects in vascular development and angiogenesis. 3. that will be complemented by in vitro analyses using FN-null endothelial cells and recombinant FN isoforms to test at the cell biological level their effects on the cells. 4. we will continue to investigate in depth the roles of various integrins in angiogenesis, with particular focus on integrins that act as FN receptors in the vasculature. 5. we will investigate contributions of FN and its splice isoforms to hemostasis and thrombosis using in vivo, ex vivo and in vitro approaches continuing our longstanding interest in this question and our recent collaborations on this topic with Dr. Wagner. 6. we have initiated and will expand a collaboration with Dr. Krieger to combine our expertise on adhesion and our mouse strains altered in many relevant adhesion receptors and ECM proteins with Dr. Krieger's expertise in coronary heart disease (CHD) and his mouse models of CHD.