PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES

描述(申请人提供)：在人类中，转化生长因子β(TGFb)家族的42个多肽控制着各种各样的细胞反应。它们在维持正常的细胞内稳态，包括正常的肿瘤抑制方面发挥着重要作用，并且在发育过程中起着关键作用。在过去的十年里，人们在理解TGFb信号方面做了大量的工作，导致了对调节这一过程的机制的重大见解。当生长因子配体与细胞表面的I型和II型信号受体结合时，信号传递过程被诱导。在人类细胞中发现的各种类型的I型和II型受体，分别有7种和5种，已被证明对TGFb样配体亚群(如TGFb、激活素或BMPs的特异性)具有广泛的特异性。然而，实现特异性的总体机制和支配特异性的决定因素尚未确定。到目前为止，对TGFb、激活素和BMP系统进行的结构研究揭示了一个意想不到的观察结果，即特异性不仅通过配体-受体接触的变化实现，而且通过整体组装模式的变化实现。这项建议的具体目标是确定激活素配体亚基诱导激活素Ib和激活素II受体协同组装的总体机制。这些研究的结果将通过定义可能是有限数量的组装模式之一来补充我们对TGFb家族中配体-受体特异性是如何实现的总体理解。

DESCRIPTION (provided by applicant): In humans, the 42 polypeptides of the transforming growth factor beta (TGFB) 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 TGFB 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 TGFB-like ligands (such as those specific for TGFB, 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 TGFB, 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 cooperative 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 TGFB family by defining what is likely to be one of a limited number of assembly modes.