MECHANISMS OF NEUROTROPHIN RECEPTOR CROSSTALK

描述（改编自申请人的摘要）：神经营养因子是一个家族， 生长因子，有助于调节生存和分化， 神经元它们通过与两个分子相互作用来影响细胞行为 不同的受体，Trk酪氨酸激酶家族的受体和低的 亲和p75NTR受体。后一种受体可以不依赖于 trk家族，通过神经酰胺的产生调节细胞死亡。此外，本发明还提供了一种方法， 似乎p75可以增加Trk的活性，相反，Trk 可以沉默p75信号;也就是说，似乎存在相互作用， 在这些受体之间。有证据表明，这些信号事件是 起始于小窝和小窝相关结构域（CRD）、富脂结构域 富含胆固醇，糖脂和特定蛋白质，包括关键的 蛋白质成分小窝蛋白。有待检验的一般假设是， "神经营养因子受体在小窝/CRD内的区室化和 这些受体与这些结构域中的结构蛋白的相互作用是 调节神经营养因子信号的关键。"为了验证这一假设， 提出了三个具体目标：在第一个目标中，提出了实验， 确定CRD的结构蛋白如何与Trk受体相互作用， 调节信号。研究人员会问， trk受体实际上调节与小窝蛋白的相互作用;如果所谓的 小窝蛋白中的支架结构域调节Trk和p75之间的相互作用 受体;如果CRD中存在的其他结构蛋白与小窝蛋白相互作用， 特别是flottlin;并询问抑制酪氨酸的机制 通过小窝蛋白激活。第二个目标是进行调查 关于CRD中通过p75信号传导抑制Trk的分子机制。 特别是，配体激活的鞘磷脂酶定位的机制， 将通过确定Trk激活细胞膜的 PI3K/PKB（Akt）通路，以及酸性磷酸酶中某些序列的磷酸化 鞘磷脂酶，调节酸性鞘磷脂酶活性。在目标三中， 脂质组合物在调节细胞的分配和信号传导中的作用 将评估CRD中的神经营养因子受体。这些研究将决定 如果将受体区室化为CRD实际上是必要的，并且如果 胆固醇和鞘磷脂的CRD含量影响 Trk到CRD，并妥协信令。

DESCRIPTION (Adapted from applicant's abstract): Neurotrophins are a family of growth factors that help to regulate the survival and differentiation of neurons. They influence cellular behavior through their interaction with two distinct receptors, the Trk tyrosine kinase family of receptors and the low affinity p75NTR receptor. The latter receptor can signal independently of the Trk family, regulating cell death via the generation of ceramide. In addition, it appears that p75 can increase the activity of Trk, and in contrast, that Trk can silence p75 signaling; that is, there seems to be reciprocal interactions between these receptors. There is evidence that these signaling events are initiated in caveolae and caveolae related domains (CRD), lipid-rich domains enriched in cholesterol, glycolipids and specific proteins, including the key protein component caveolin. The general hypothesis to be tested is that "compartmentalization of neurotrophin receptors within caveolae/CRDs and the interaction of these receptors with structural proteins in these domains is critical for the regulation neurotrophin signaling." To test this hypothesis, three specific aims are proposed: In the first aim, experiments are proposed to determine how structural proteins of CRDs interact with Trk receptors and regulate signaling. The investigators will ask if a putative binding domain in Trk receptors in fact regulate interactions with caveolin; if so-called scaffolding domains in caveolin regulates interactions between Trk and p75 receptors; if other structural proteins present in CRDs interact with caveolin, in particular, flottlin; and ask about the mechanism of inhibition of tyrosine activation by caveolin. In the second aim, investigations will be made regarding the molecular mechanism of Trk inhibition by p75 signaling in CRDs. In particular, the mechanism of a ligand-activated sphingomyelinase localized in caveolae will be investigated by determining if Trk activation of the PI3K/PKB (Akt) pathway, and phosphorylation of certain sequences in acid sphingomyelinase, regulate acid sphingomyelinase activity. In aim three, the effect of the lipid composition in regulating the partitioning and signaling of neurotrophin receptors in CRDs will be assessed. These studies will determine if compartmentalization of the receptors into CRDs is in fact necessary, and if the CRD content of cholesterol and sphingomyelin affects the localization of Trk to CRDs, and compromises signaling.