Functions of BPAG1n

神经营养因子支持中枢和外周神经元的存活、生长和突触。 神经营养因子作用的高度特异性和保真度部分归因于它们激活高密度脂蛋白 亲和力细胞表面受体。神经营养因子，第一个被发现的神经营养因子家族就是例证 通过原型成员神经生长因子(NGF)，通过激活其受体酪氨酸激酶发挥作用 (RTKs)，Trks。第二个营养因子家族，胶质细胞源性神经营养因子(GDNF) 家族配体(GFL)通过激活其RTK、Ret发挥功能。我们最近发现了一个内部RTK NGF受体TrkA激活的信号机制在体外和体内都导致 在没有GFLS的情况下，成熟依赖的激活Ret。NGF介导的Ret激活增强血管内皮细胞 成熟的，但不是未成熟的交感神经元的营养状态。为了确定通过什么机制 NGF促进Ret激活，生化实验旨在系统测试最有可能的 利用体外培养的成熟交感神经元，提出了假说。身份的鉴定 NGF促进Ret活化的机制对于形成长期的 揭示哪些受体参与RTK间信号转导，以及这一信号在发育过程中的作用 流程已经完成了。为了识别GFL依赖和GFL非依赖(即NGF依赖)RET 体内转基因动物的功能要么是所有Ret功能缺陷，要么是只有Ret功能缺陷 依赖于GFL的Ret函数。对这些人的中枢和周围神经系统的详细检查 鉴于Ret缺乏对围产期的致命性，动物将首次揭示Ret的出生后功能 不允许检查出生后发育的动物。作为首席调查员，我将学到一个 重要实验技能的新技能，例如在 解剖、生理和行为水平，以及慢病毒载体的生产 初级神经元中的外来蛋白。这些拟议的实验的结果以及这些技术是 会学习，会为我追求我的职业目标，建立一个独立的研究提供坚实的基础 作为一个学术实验室的首席调查员。

Neurotrophlc tactors support the survival, growth, and d]tterentxation of both central and peripheral neurons. The great specificity and fidelity of the effects ofneurotrophic factors are due in part to their activation of high affinity cell surface receptors. The neurotrophins, the first identified family of neurotrophic factors exemplified by the prototypical member nerve growth factor (NGF), function via activation of their receptor tyrosine kinases (RTKs), the Trks. A second family oftrophic factors, the glial cell-line derived nenrotrophic factor (GDNF) family ligands (GFLs), function via activation of their RTK, Ret. We have recently identified an inter-RTK signaling mechanism by which activation of the NGF receptor, TrkA, leads both in vitro and in vivo to the maturation-dependent activation Ret in the absence of GFLs. NGF-mediated Ret activation augments the trophic status of mature, but not immature, sympathetic neurons. In order to identify the mechanism by which NGF promotes Ret activation, biochemical experiments designed to systematically test the most likely hypotheses are proposed, making use of mature sympathetic neurons maintained in vitro. The identification of the mechanism by which NGF promotes Ret activation is critically important for the formation of a long-term project to reveal which receptors participate in inter-RTK signaling, and what developmental functions this process has. In order to identify both the GFL-dependent and GFL-independent (i.e. NGF-dependent) Ret functions in vivo transgenie animals will be produced that are deficient in either all Ret functions, or in only GFL-dependent Ret functions. A detailed examination of the central and peripheral nervous systems of these animals will reveal, for the first time, the postnatal functions of Ret, given the perinatal lethality of Ret deficient animals that has not allowed examination of postnatal development. As the principle investigator I will leam a new repertoire of important experimental skills, such as the production and analysis oftransgenic animals at the anatomic, physiologic, and behavioral levels, as well as the production of lentiviral vectors for the expression of foreign proteins in primary neurons. The results from these proposed experiments, as well as the techniques I will learn, will provide a solid basis for me to pursue my career objective to establish an independent research program as the principle investigator of an academic laboratory.