PDGF Receptor Signaling in Mammalian Development

描述（由申请方提供）：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）的发育和功能中发挥重要作用。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，导致增殖、分化和迁移。虽然受体的信号转导已经研究了很多年，但它们在体内的作用仍然是难以捉摸的。该提案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，并将这些知识应用于了解该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，已经产生了一组小鼠，它们提供了研究活组织中信号转导的独特机会。这些小鼠将被用于一系列实验，旨在解决心脏，肾脏和眼睛中生化信号的作用。该提议的具体目的是：1）研究PDGFR α在壁细胞（血管平滑肌细胞和周细胞）的发育和信号转导中的功能;和2）鉴定哺乳动物胚胎发生期间两种PDGF受体下游的磷酸肌醇-3激酶的功能。从这些研究中获得的知识将提供有关哺乳动物组织内受体介导的细胞内信号转导机制的重要信息。此外，这些实验将提供有关间充质细胞中PDGF受体功能的必要细节，特别是那些为血管提供支持的细胞。这种理解可能导致在发育和疾病状态期间控制这种细胞群体的新方法。

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.