PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES

在人类中，转化生长因子β（TGF β）家族的42种多肽控制各种各样的免疫调节。 细胞反应。它们在维持正常的细胞内稳态，包括正常的 肿瘤抑制，它们在发育中起着关键作用。在过去的十年里， 旨在了解TGF β信号传导，导致有关机制的重要见解， 规范这个过程。当生长因子配体与I型和II型受体结合时， II型信号受体。在人类中鉴定的各种I型和II型受体 细胞，其中有七个和五个，分别，已被证明表现出广泛的特异性， TGF β样配体的亚组（如对TGF β、激活素或BMP特异的那些）。整体 实现特异性的机制和控制特异性的决定因素， 被定义。迄今为止用TGF β、激活素和BMP系统进行的结构研究已经揭示了 特异性不是通过配体-受体接触的变化而获得的出乎意料的观察结果 单独地，但也通过整个组装模式的变化。这项建议的具体目标是 定义激活素配体亚组诱导协同组装的总体机制 激活素Ib型和激活素II型受体。这些研究的结果将 补充了我们对TGF β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组装模式之一。

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.