PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES

在人类中，转化生长因子β(TGFp)家族的42个多肽控制着多种不同的 细胞反应。它们在维持正常的细胞内稳态方面发挥着重要作用，包括正常的 肿瘤抑制，它们在发育过程中起着关键作用。在过去的十年中，已经做出了重大努力 旨在了解TGFp信号转导，从而对 规范这一过程。当生长因子配体与I型和I型结合时，信号转导过程被诱导 细胞表面的II型信号受体。人类多种类型的I型和II型受体 细胞，其中分别有7个和5个，已被证明具有广泛的特异性 TGFp类配体的亚群(如那些TGFp、激活素或BMP的特异性配体)。整体而言 然而，实现特异性的机制和支配特异性的决定因素并没有 已经被定义了。到目前为止对TGFp、激活素和BMP系统进行的结构研究揭示了 意想不到的观察到，特异性并不是通过配体-受体接触的变化来实现的 单独，但也通过整体组装模式的变化。这项提议的具体目标是 为了确定配体激活素亚基诱导协同组装的总体机制 激活素Ib型和激活素II型受体。从这些研究中得出的发现将 补充我们对TGFp家族如何实现配体-受体特异性的整体理解 定义什么可能是有限数量的装配模式之一。

In humans, the 42 polypeptides of the transforming growth factor beta (TGFp) family control a wide variety of cellular responses. They play important roles in maintaining normal cellular homeostasis, including normal tumor suppression, and they play key roles in development. Over the last decade, significant effort has been directed toward understanding TGFp signaling, leading to significant insights regarding mechanisms that regulate this process. The signaling process is induced when the growth factor ligands bind to type I and type II signaling receptors on the cell surface. The various type I and type II receptors identified in human cells, of which there are seven and five, respectively, have been shown to exhibit broad specificity for subgroups of TGFp-like ligands (such as those specific for TGFp, activin, or BMPs). The overall mechanisms by which specificity is achieved and the determinants that govern specificity however have not been defined. Structural studies conducted thus far with the TGFp, activin, and BMP systems have revealed the unexpected observation that specificity is achieved not through variation in ligand-receptor contacts alone, but through variation in the overall assembly mode as well. The specific objective of this proposal is to define the overall mechanism by which the activin subgroup of ligands induces the coopera tive assembly of the activin type Ib and activin type II receptors. The findings that emerge from these studies will complement our overall understanding of how ligand-receptor specificity is achieved in the TGFp family by defining what is likely to be one of a limited number of assembly modes.