PDGF Receptor Signaling in Mammalian Development

描述（由申请人提供）：血小板衍生生长因子受体（PDGFRa和PDGFRa）是受体酪氨酸激酶，在许多间充质细胞类型（包括血管平滑肌细胞和肺泡平滑肌细胞）的发育和功能中起重要作用。当这些受体结合配体时，它们能够激活细胞内的多种信号转导途径，导致细胞的增殖、分化和迁移。虽然受体的信号转导研究已经进行了很多年，但它们在体内的作用仍然是难以捉摸的。本研究的长期目标是了解这些信号转导途径如何转化为细胞反应，并应用这些知识来理解这一受体家族在血管生物学和间充质细胞发育中的功能。为了实现这一目标，一组小鼠提供了独特的机会来研究活组织中的信号转导。这些小鼠将被用于一系列的实验，旨在解决生化信号在心脏、肾脏和眼睛中的作用。本课题的具体目的是：1)研究PDGFRa在壁细胞（血管平滑肌细胞和周细胞）发育和信号转导中的功能；2)确定两种PDGF受体下游的磷酸肌苷-3激酶在哺乳动物胚胎发生中的功能。从这些研究中获得的知识将为哺乳动物组织中受体介导的细胞内信号转导机制提供重要信息。此外，这些实验将为PDGF受体在间充质细胞中的功能提供必要的细节，特别是那些为血管提供支持的细胞。这种理解可能会导致在发育和疾病状态下控制这种细胞群的新方法。

DESCRIPTION (provided by applicant): Platelet derived growth factor receptors (PDGFRa and PDGFRa) are receptor tyrosine kinases that play an important role in the development and function of many mesenchymal cell types including vascular smooth muscle cells and lung alveolar smooth muscle cells. When these receptors bind ligand, they are capable of activating a multitude of signal transduction pathways within the cell, resulting in proliferation, differentiation, and migration. Although the receptors' signal transduction has been studied for many years, their roles in vivo remain elusive. The long term goals of this proposal are to understand how these signal transduction pathways translate to cellular responses and apply this knowledge to understanding the function of this family of receptors in vascular biology and mesenchymal cell development. To attain this goal, a panel of mice that afford the unique opportunity to investigate signal transduction in living tissues has been generated. These mice will be used in a series of experiments designed to address the role of biochemical signals in the heart, the kidney, and the eye. The specific aims of this proposal are to: 1) study the function of the PDGFRa in development and signal transduction of mural cells (vascular smooth muscle cells and pericytes); and 2) identify the function of phosphoinositide-3 kinase downstream of both PDGF receptors during mammalian embryogenesis. The knowledge gained from these studies will provide essential information regarding the mechanisms of receptor mediated intracellular signal transduction within mammalian tissues. In addition, these experiments will offer necessary details regarding the function of PDGF receptors in mesenchymal cells especially those that provide support for blood vessels. This understanding could lead to novel approaches for controlling this cell population during development and in disease states.