Signaling in endothelial growth & angiogenesis

内皮生长中的信号传导

基本信息

批准号：
8645676
负责人：
Xinchun Pi
金额：
$ 37.24万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8645676
关键词：
Accounting Address Adult Affect Angioblast Applications Grants Area BMP4 Biochemical Biology Blood Vessels Bone Morphogenetic Proteins Cardiovascular Diseases Cardiovascular system Cellular biology Chronic Complex Coronary Coronary artery Data Defect Development Differentiation and Growth Distal Embryo Embryonic Development Endothelial Cells Event Functional disorder Funding Gene Expression Genetic Goals Grant Growth Healed Hematological Disease In Vitro Individual Influentials Injury Knowledge Laboratories Mediating Mediation Molecular Molecular Profiling Natural regeneration Nature Organ Pathway interactions Physiological Play Process Protein Binding Proteins Public Health Regulation Role Signal Pathway Signal Transduction Sorting - Cell Movement Stimulus Stress System Techniques Testing Therapeutic Tissues Tumor Biology Vascular Endothelium Vascular remodeling Work angiogenesis base bone morphogenetic protein receptors cell motility clinically relevant design expectation extracellular healing in vivo migration novel pleiotropism protein activation protein complex public health relevance receptor research study response semilunar valve success tumor growth vasculogenesis zebrafish development

Accounting Address Adult Affect Angioblast Applications Grants Area BMP4 Biochemical Biology Blood Vessels Bone Morphogenetic Proteins Cardiovascular Diseases Cardiovascular system Cellular biology Chronic Complex Coronary Coronary artery Data Defect Development Differentiation and Growth Distal Embryo Embryonic Development Endothelial Cells Event Functional disorder Funding Gene Expression Genetic Goals Grant Growth Healed Hematological Disease In Vitro Individual Influentials Injury Knowledge Laboratories Mediating Mediation Molecular Molecular Profiling Natural regeneration Nature Organ Pathway interactions Physiological Play Process Protein Binding Proteins Public Health Regulation Role Signal Pathway Signal Transduction Sorting - Cell Movement Stimulus Stress System Techniques Testing Therapeutic Tissues Tumor Biology Vascular Endothelium Vascular remodeling Work angiogenesis base bone morphogenetic protein receptors cell motility clinically relevant design expectation extracellular healing in vivo migration novel pleiotropism protein activation protein complex public health relevance receptor research study response semilunar valve success tumor growth vasculogenesis zebrafish development

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项目摘要

DESCRIPTION (provided by applicant): In this grant proposal we seek to characterize how BMPER, an extracellular regulator of the BMP signaling pathway, influences the biology and function of endothelial cells. Understanding the biology of endothelial cells and the signaling pathways they use in order to orchestrate their pleiotropy of function is of critical importance given the vast array of cardiovascular, circulatory and blood diseases that result from the dysfunction of the vascular endothelium. Work in our laboratory and others has revealed that BMPER, through it's mediation of BMP signaling events, is critically involved in numerous aspects of endothelial cell biology that impinge on and affect vascular development in the embryo and the success of revascularization in mature tissues. Defining the mechanism behind BMPER's ability to affect these processes, however, has been complicated due to the unusual ability of BMPER to both promote and inhibit BMP activity in a context-dependent manner. Recently, we have discovered that BMPER modulates BMP4 activity via a concentration-dependent, endocytic trap-and- sink mechanism, with low levels of BMPER promoting and high levels inhibiting BMP4 signaling, thereby accounting for the biphasic nature of BMPER's regulation of BMP4 activity. Furthermore, we found that the differential recruitment of receptor complex proteins, determined by the concentration ratio of BMPER to BMP4, predisposes the BMPER/BMP4 signaling complex to be sorted by intracellular compartments that result in either the enhancement or inhibition of BMP activation. Here we propose to build on these findings by using a novel and highly integrated approach in which vascular events at the molecular, transcriptional, and genetic level will be related to pathologically and therapeutically relevant processes within the endothelial compartment. Specifically, we propose to: 1). Understand the broad biochemical regulation of BMPER activity in endothelial cells; 2). Elucidate the role of BMPER in the regulation of signaling events necessary for endothelial cell migration; and 3). Determine the role of BMPER-mediated signaling during coronary angiogenesis, a process that until now, has not been explored in terms of BMPER/BMP signaling but which our preliminary data demonstrate is reliant on BMPER. The aims of this grant are a logical extension of work done in the previous cycle. We anticipate that this approach, while challenging in its scope, will allow the individual parts of the project to be synergistic without being interdependent on one another for completion, should problems arise in one area.

描述（由申请人提供）：在此赠款建议中，我们试图表征BMPER是BMPER是BMP信号通路的细胞外调节剂如何影响内皮细胞的生物学和功能。鉴于由于血管内皮的血管功能障碍引起的大量心血管，循环和血液疾病，了解内皮细胞的生物学以及为了策划其功能的多效性而使用的信号通路至关重要。我们实验室和其他人的工作表明，通过对BMP信号事件的调解，BMPER与内皮细胞生物学的许多方面有关，这些方面影响并影响胚胎中的血管发育以及成熟组织中血运重建的成功。但是，由于BMPER以上下文依赖性的方式促进和抑制BMP活性的异常能力，确定BMPER影响这些过程的能力背后的机制变得复杂。最近，我们发现BMPER通过浓度依赖性的内吞陷阱和水槽机制调节BMP4活性，其BMPER促进的水平较低，高水平抑制BMP4信号，从而考虑了BMPER对BMP4活性调节的双重性质。此外，我们发现受体复合蛋白的差异募集，由BMPER与BMP4的浓度比确定，使BMPER/BMP4信号传导复合物倾向于通过细胞内隔室进行排序，从而导致BMP激活的增强或抑制。在这里，我们建议通过使用一种新颖且高度集成的方法来建立这些发现，在这种发现中，在这种方法中，分子，转录和遗传水平的血管事件将与内皮隔室内的病理和治疗相关的过程有关。具体来说，我们建议：1）。了解内皮细胞BMPER活性的广泛生化调节； 2）。阐明BMPER在调节内皮细胞迁移所必需的信号事件中的作用；和3）。确定BMPER介导的信号传导在冠状血管生成过程中的作用，这一过程尚未根据BMPER/BMP信号传导探索，但我们的初步数据证明这是依赖BMPER的。这笔赠款的目的是对上一个周期中完成的工作的逻辑扩展。我们预计，这种方法在其范围上具有挑战性，但如果在一个领域出现问题，那么项目的各个部分就可以保持协同作用而不会相互依存。