T lymphocyte growth regulation by prointerleukin-16

描述(由申请者提供)：这份建议书描述了一项为期5年的培训计划，旨在发展肺部医学和免疫学的学术生涯。这位首席研究员已经完成了马萨诸塞州综合医院的内科住院医师计划，并已进入波士顿大学医学院肺部和危重护理医学奖学金计划的最后一年。他现在寻求通过整合智力、教育和技术资源来扩展他的科学技能。这一计划将促进T淋巴细胞激活和增殖领域的专业知识应用于肺部免疫疾病。大卫中心将指导首席调查员的科学发展。Center博士是T细胞生物学领域公认的领导者。他是肺和重症监护医学系主任，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建议。研究重点将集中在前白介素16(Pro-IL-16)对T细胞激活和增殖的调节。前IL-16是一种丰富的T细胞胞核和胞浆蛋白。我们的实验室已经证明，Pro-IL-16是一种有效的T细胞生长抑制因子，其主要作用是阻止细胞周期于G0/G1期。这与细胞周期抑制因子p27KIP1在泛素连接酶F盒蛋白Skp2降低后显著升高有关，泛素连接酶F盒蛋白Skp2与p27KIP1降解有关。沿着这些途径，随着T细胞受体(TCR)的激活，Pro-LL-16mRNA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，核前-IL-16的丢失对细胞周期进程是必不可少的。我们将通过以下方式验证这一假设：1)通过微阵列分析确定影响TCR依赖的激活和生长的前-IL-16调节基因，以及2)确定选定的细胞周期相关基因的前-LL-16调节的功能意义。波士顿大学医学院肺中心通过将来自不同资源的专业知识整合到个性化的项目中，以满足研究人员的兴趣和技能，为培训内科科学家提供了理想的环境。这样的环境最大限度地增加了首席研究员建立一个科学利基的潜力，从这个利基上可以建立一个学术生涯。

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.