Structure and function of integrin TM and CYTO domains

描述（由申请人提供）：候选人的职业目标是成为一名独立的研究者，专注于整合素介导的信号通路的分子机制，并采用跨学科的方法。许多整合素在细胞发育和迁移中起着至关重要的作用，因此被确定为癌症治疗的潜在药物靶点。在短期内，候选人寻求了解整合素alphaIIbbeta3的跨膜和细胞质（TM-CYTO）结构域的作用，使用结构和细胞生物学方法的结合。这项研究的结果将有助于更好地了解癌症生物学和抗癌药物的开发。为此，他发起了对alphaIIb和beta3TM-CYTO结构域对应的膜结合蛋白的研究，并假设了这些蛋白在整合素激活和聚类背景下的同质寡聚化意义。该项目的具体目标是：(1)确定？的TM-CYTO域的解结构。3亚基核磁共振光谱。(2)表征？b和？生物膜中的3TM-CYTO结构域，并识别破坏或增强自结合的点突变。基于细菌的TOXCAT系统将用于此目的。(3)研究同源寡聚化对中国仓鼠卵巢细胞和/或GM1500 b淋巴细胞alphaIIbbeta3功能的影响。接下来的一两年将是候选人磨练他的研究技能的关键，并为整合素领域做出重大贡献，从而允许平稳过渡到独立。他的赞助人，威廉·迪戈博士，有着出色的指导记录。主办方实验室和生物化学与生物物理系有支持和激励的氛围，鼓励科学交流与合作，这有利于候选人作为科学家的发展。

DESCRIPTION (provided by applicant): The candidate's career goal is to become an independent investigator focused on the molecular mechanisms of the integrin-mediated signaling pathway with an interdisciplinary approach. Many integrins are critically involved in cell development and migration, and accordingly identified as potential drug targets for cancer treatment. In the short term, the candidate seeks to understand the roles of the transmembrane and cytoplasmic (TM-CYTO) domains of integrin alphaIIbbeta3, using a combination of structural and cell biology methods. The results acquired from this study will contribute to a better understanding of cancer biology and the development of anti-cancer agents. To this end, he has initiated studies on the membrane-bound proteins corresponding to alphaIIb and beta3TM-CYTO domains, and hypothesized the significance of homo-oligomerization of these proteins in the context of integrin activation and clustering. The specific aims of this project are: (1) To determine the solution structure of the TM-CYTO domains of ?3 subunit by NMR spectroscopy. (2) To characterize homo-oligomerization of the ?IIb and ?3TM-CYTO domains in biological membranes and identify point mutations that disrupt or enhance self-association. The bacteria-based TOXCAT system will be used for this purpose. (3) To study the effects of homo-oligomerization on alphaIIbbeta3 function in GM1500 B-lymphocytes and/or Chinese hamster ovary cells. The next year or two will be critical for the candidate to polish his research skills, and make a significant contribution to the integrin field, thus allowing for a smooth transition to independence. His sponsor, Dr. William DeGrado, has an excellent mentoring track record. There is a supportive and stimulating atmosphere in the sponsor's lab and the Department of Biochemistry and Biophysics that encourages scientific exchange and collaboration, which is beneficial to the candidate's development as a scientist.