T lymphocyte growth regulation by prointerleukin-16

白介素原 16 对 T 淋巴细胞生长的调节

• 批准号: 6671532
• 负责人: Kevin C WILSON
• 金额: $ 12.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-04 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6671532
• 关键词: T lymphocyte; amidohydrolases; cell cycle; cell growth regulation; cytogenetics; cytokine; leukocyte activation /transformation; lymphocyte proliferation; molecular chaperones; protein localization; protein structure function

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in pulmonary medicine and immunology. The principle investigator has completed a residency program in Internal Medicine at Massachusetts General Hospital and is in the final year of a fellowship program in Pulmonary and Critical Care Medicine at Boston University School of Medicine. He now seeks to expand upon his scientific skills through an integration of intellectual, educational, and technical resources. This program will promote expertise in the area of T lymphocyte activation and proliferation as applied to pulmonary immune diseases. David Center will mentor the principle investigator's scientific development. Dr. Center is a recognized leader in the field of T cell biology. He is the Chief of Pulmonary and Critical Care Medicine and has trained numerous post-doctoral fellows and graduate students. In addition, an advisory committee of highly regarded medical scientists will provide scientific and career advice. Research will focus on regulation of T cell activation and proliferation by prointerleukin-16 (pro-lL-16). Pro- IL-16 is an abundant T cell nuclear and cytoplasmic protein. Our laboratory has demonstrated that pro-lL-16 is a potent suppressor of T cell growth, whose major affect is to arrest the cell cycle in G0/G1. This is associated with marked rises in the cell cycle inhibitor p27KIP1 following decreases in the ubiquitin ligase F box protein Skp2 which is associated with p27KIP1 degradation. Along these lines, following T cell receptor (TcR) activation, pro-lL-16 mRNA is markedly downregulated and pro-lL-16 protein disappears from the nucleus prior to cell cycle progression. Our hypothesis is that loss of nuclear pro-lL-16 is essential for cell cycle progression. We will test this hypothesis by: 1) Identifying pro-lL-16-regulated genes by microarray analyses that affect TcR-dependent activation and growth and 2) Determining the functional significance of pro-lL-16 regulation of selected cell cycle related genes. The Pulmonary Center of Boston University School of Medicine provides an ideal setting for training physician-scientists by incorporating expertise from diverse resources into programs individualized to meet the investigator's interests and skills. Such an environment maximizes the potential for the principle investigator to establish a scientific niche from which an academic career can be constructed.

描述（由申请人提供）：此提案描述了一个为期5年的肺医学和免疫学学术生涯发展的培训计划。主要研究者已经完成了马萨诸塞州总医院内科的住院医师项目，目前是波士顿大学医学院肺部和重症监护医学的最后一年奖学金项目。他现在寻求通过智力、教育和技术资源的整合来扩展他的科学技能。该计划将促进T淋巴细胞活化和增殖领域的专业知识应用于肺部免疫疾病。大卫中心将指导主要研究者的科学发展。Center博士是T细胞生物学领域公认的领导者。他是肺和重症医学主任，培养了许多博士后研究员和研究生。此外，一个由备受尊敬的医学科学家组成的咨询委员会将提供科学和职业咨询。研究将集中于白细胞介素-16 （pro-l -16）对T细胞活化和增殖的调控。Pro- IL-16是一种丰富的T细胞核和细胞质蛋白。我们的实验室已经证明，pro-l -16是T细胞生长的有效抑制因子，其主要作用是在G0/G1期阻滞细胞周期。这与与p27KIP1降解相关的泛素连接酶F盒蛋白Skp2降低后细胞周期抑制剂p27KIP1显著升高有关。沿着这些思路，在T细胞受体（TcR）激活后，pro-lL-16 mRNA显著下调，pro-lL-16蛋白在细胞周期进展之前从细胞核中消失。我们的假设是细胞核pro-l -16的丢失对细胞周期的进展是必不可少的。我们将通过以下方法来验证这一假设：1)通过微阵列分析鉴定影响tcr依赖性激活和生长的pro-lL-16调控基因；2)确定pro-lL-16调控选定细胞周期相关基因的功能意义。波士顿大学医学院肺科中心通过将来自不同资源的专业知识整合到个性化项目中，以满足研究者的兴趣和技能，为培训医师科学家提供了理想的环境。这样的环境最大限度地发挥了主要研究者建立科学利基的潜力，从而可以构建学术生涯。