Pyk2 Signaling In Intestinal Epithelial Cells

肠上皮细胞中的 Pyk2 信号转导

• 批准号: 6507911
• 负责人: STEVEN S WU
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6507911
• 关键词: DNA replication; G protein; angiotensin II; biological signal transduction; cell migration; cell proliferation; cytoskeleton; gastrointestinal epithelium; lysophospholipids; mitogen activated protein kinase; phosphorylation; protein tyrosine kinase; receptor; receptor coupling; tissue /cell culture

DESCRIPTION (provided by applicant): My long-term goal is to achieve an academic career in medicine, continue to teach, and to establish an independent program of research in the field of gastrointestinal signal transduction. At the same time, I wish to continue in the practice of clinical medicine, and ultimately to contribute to the advancement of basic research as it relates to health. In particular, though my work analyzes molecular mechanisms of cell signaling, I aim to study these with an eye towards developmental processes, such as intestinal growth and maturation, or towards issues important to both adult and child populations, such as inflammatory bowel disease. My more immediate priority is to obtain grant support in order to continue both my research and my growth as a scientist. I seek an environment for my initial junior faculty position that will provide me with both a depth of resources to stimulate scientific growth, and a strong commitment to protected research time. I have chosen UCLA and my mentor, Dr. Enrique Rozengurt, because of his expertise in the field of signal transduction, the resources of the university, and the commitment of Dr. Rozengurt and of the Department of Pediatrics to support my training. This research proposal focuses on understanding the mechanisms by which environmental signals are translated into cellular functions in intestinal epithelia. Intestinal epithelial cell functions, including growth, migration, and differentiation, are regulated by a wide variety of soluble and contact-dependent stimuli. The IEC-6 and IEC-18 small intestinal epithelial cell lines have been widely used as models of proliferation and wound restitution. Specifically, we aim to study signaling pathways in the response to G protein-coupled receptor (GPCR) agonists. The central hypothesis we will address is that the cytoplasmic tyrosine kinase Pyk2 acts to integrate multiple signals in intestinal epithelial cells and plays a key role in mediating their cellular effects. Our first specific aim is to study the regulation of Pyk2 by phosphorylation at distinct sites, and by interactions with other signaling proteins, following stimulation of GPCR signaling. Our second aim is to correlate Pyk2 activity to cytoskeletal structure and function. The third aim is to evaluate the role of Pyk2 in regulating DNA synthesis and cell motility. By elucidating key signal transduction pathways in the intestinal epithelium, we will better understand the mechanisms underlying the processes of growth, wound healing, and neoplasia in the GI epithelium.

描述(由申请人提供)： 我的长期目标是在医学领域实现学术生涯，继续任教，并在胃肠道信号转导领域建立独立的研究项目。与此同时，我希望继续从事临床医学工作，并最终为促进与健康有关的基础研究做出贡献。特别是，尽管我的工作分析了细胞信号的分子机制，但我的目标是研究这些机制，着眼于发育过程，如肠道生长和成熟，或对成人和儿童群体都重要的问题，如炎症性肠道疾病。 我的当务之急是获得拨款支持，以便继续我的研究和作为一名科学家的成长。我为我最初的初级教员职位寻找一个环境，这个环境将为我提供深度的资源来刺激科学发展，并坚定地致力于保护研究时间。我选择了加州大学洛杉矶分校和我的导师Enrique Rozengurt博士，因为他在信号转导领域的专业知识，大学的资源，以及Rozengurt博士和儿科承诺支持我的培训。 这项研究计划侧重于了解环境信号在肠道上皮细胞中转化为细胞功能的机制。肠上皮细胞的功能，包括生长、迁移和分化，受多种可溶性和接触性刺激的调节。IEC-6和IEC-18小肠上皮细胞系已被广泛用作增殖和创面修复的模型。具体来说，我们的目标是研究G蛋白偶联受体(GPCR)激动剂反应中的信号通路。我们将解决的中心假设是，细胞质酪氨酸激酶Pyk2在肠道上皮细胞中整合多种信号，并在介导它们的细胞效应中发挥关键作用。我们的第一个特定目标是研究不同位点的磷酸化以及在GPCR信号刺激后与其他信号蛋白的相互作用对Pyk2的调节。我们的第二个目标是将Pyk2活性与细胞骨架结构和功能联系起来。第三个目的是评估Pyk2在调节DNA合成和细胞运动中的作用。通过阐明肠道上皮细胞中的关键信号转导通路，我们将更好地了解胃肠道上皮细胞生长、伤口愈合和肿瘤发生的机制。