Chemical Genetics of Vertebrate Vascular Development

脊椎动物血管发育的化学遗传学

• 批准号: 7234118
• 负责人: CHARLES C HONG
• 金额: $ 13.37万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234118
• 关键词: 1-Phosphatidylinositol 3-Kinase; Alleles; Angioblast; Aorta; Biological; Biology; Blood Vessels; Cardiology; Cardiovascular system; Cell physiology; Chemical Structure; Chemicals; Clinical; Data; Defect; Detection; Development; Developmental Process; Embryo; Embryonic arterial structure; Endothelial Cells; Evolution; Fellowship; Fluorescence Microscopy; Genes; Genetic; Human; In Vitro; LY294002; Lead; Lesion; Light; MEKs; Mediating; Methods; Molecular; Molecular Biology; Molecular Genetics; Mutation; Numbers; Organogenesis; Pathway interactions; Phenotype; Phosphatidylinositide 3-Kinase Inhibitor; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Production; Research; Research Personnel; Resources; Role; Seminal; Series; Signal Pathway; Signal Transduction; Staging; Structure; Techniques; Testing; Tissues; Training; Umbilical vein; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Veins; Venous; Work; Zebrafish; angiogenesis; base; chemical genetics; developmental genetics; enhanced green fluorescent protein; genetic analysis; genetic manipulation; in vivo; kinase inhibitor; migration; mutant; neutralizing antibody; notch protein; novel; precursor cell; progenitor; programs; research study; response; skills; small molecule; tool; vasculogenesis

DESCRIPTION (provided by applicant): Understanding how the vertebrate circulatory system develops is a fundamental biological challenge with tremendous clinical implications. Molecular and genetic studies in zebrafish have highlighted the key roles of vascular endothelial growth factor (VEGF), Notch, and gridlock (grl) in the signaling pathway for embryonic vascular development. The zebrafish has proven to be remarkably amenable to chemical genetics analysis, in which small molecules discovered by high-throughput, phenotype-based screens are used as tools for dissecting cellular and developmental processes. Seminal work has recently identified a novel compound, GS4012, by virtue of its ability to suppress the vascular defect caused by a mutation in the grl gene. The grl suppressor screen has also identified another suppressor, GS4898, which has a completely different structure, and presumably distinct mechanism of action, from GS4012. This proposal takes molecular and chemical genetic approaches to study vertebrate vascular development, with three specific aims: 1) Determine how GS4012 rescues the gridlock vascular defect in mutant embryos. 2) Identify signaling pathways targeted by GS4012 in cultured endothelial cells. 3) Identify the mechanism of action of GS4898 in vivo and in vitro. This project will help to answer some of the outstanding questions regarding vasculogenesis and provide a valuable set of chemical tools for further study. Gridlock suppressors like GS4012 and GS4898, which modulate vascular development, may serve as lead compounds for treatments of important illnesses such ischemic vascular diseases. The candidate, who has a background in molecular biology and developmental genetics, has recently completed cardiology fellowship training. Dr. Hong now seeks to expand upon his scientific skills through unique resources available at the MGH's Cardiovascular Research Center. His two sponsors will guide him in chemical genetics, zebrafish biology, and cardiovascular cellular physiology, as well as in professional development. Dr. Hong's panel of advisors includes leaders in the fields of angiogenesis, zebrafish organogenesis, and zebrafish hemangioblast development. Mechanism of action studies of GS4012, GS4898, and additional gridlock suppressors will serve as a springboard for further scientific development, culminating in Dr. Hong's emergence as an independent investigator in the field of basic vascular biology.

描述（由申请人提供）： 了解脊椎动物循环系统如何发展是具有巨大临床意义的基本生物学挑战。 斑马鱼中的分子和遗传研究强调了血管内皮生长因子（VEGF），Notch和Gridlock（GRL）在胚胎血管发育的信号传导途径中的关键作用。事实证明，斑马鱼非常适合化学遗传学分析，其中通过高通量发现，基于表型的筛选被用作解剖细胞和发育过程的工具。 最近，开创性的工作确定了一种新型化合物GS4012，它抑制了由GRL基因突变引起的血管缺陷的能力。 GRL抑制器屏幕还确定了另一个抑制器GS4898，该抑制剂与GS4012具有完全不同的结构，也许是不同的作用机理。 该建议采用分子和化学遗传学方法来研究脊椎动物血管发育，三个具体目的：1）确定GS4012如何营救突变体胚胎中的僵局血管缺陷。 2）确定GS4012靶向的信号通路在培养的内皮细胞中。 3）确定GS4898在体内和体外的作用机理。 该项目将有助于回答有关血管生成的一些杰出问题，并为进一步研究提供一套宝贵的化学工具。 调节血管发育的GS4012和GS4898之类的僵局抑制剂可能是铅化合物，用于治疗重要疾病，例如缺血性血管疾病。 该候选人在分子生物学和发育遗传学方面具有背景，最近完成了心脏病学研究金培训。 Hong博士现在试图通过MGH的心血管研究中心获得的独特资源来扩展他的科学技能。 他的两个赞助商将指导他从事化学遗传学，斑马鱼生物学和心血管细胞生理学以及专业发展。 Hong博士的顾问小组包括血管生成，斑马鱼器官发生和斑马鱼血管细胞发育领域的领导者。 GS4012，GS4898和其他僵局抑制器的作用研究机制将成为进一步科学发展的跳板，最终导致了Hong博士在基本血管生物学领域的独立研究者的出现。