T lymphocyte growth regulation by prointerleukin-16

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展肺部医学和免疫学的学术生涯。主要研究者已在马萨诸塞州总医院完成了内科住院医师项目，并在波士顿大学医学院完成了肺部和重症监护医学奖学金项目的最后一年。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。该计划将促进应用于肺部免疫疾病的T淋巴细胞活化和增殖领域的专业知识。大卫中心将指导主要研究者的科学发展。Dr. Center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主任，并培养了许多博士后研究员和研究生。此外，一个由德高望重的医学科学家组成的咨询委员会将提供科学和职业建议。研究将集中于白细胞介素-16（pro-IL-16）对T细胞活化和增殖的调节。Pro-IL-16是一种丰富的T细胞核和胞浆蛋白。我们的实验室已经证明pro-IL-16是T细胞生长的有效抑制剂，其主要作用是将细胞周期阻滞在G 0/G1期。这与细胞周期抑制剂p27 KIP 1的显著升高有关，而细胞周期抑制剂p27 KIP 1的升高与泛素连接酶F盒蛋白Skp 2的降低有关，Skp 2与p27 KIP 1的降解有关。沿着这些线，在T细胞受体（TcR）活化后，pro-IL-16 mRNA显著下调，并且pro-IL-16蛋白在细胞周期进展之前从细胞核消失。我们的假设是，核pro-IL-16的丢失是细胞周期进程所必需的。我们将通过以下方式检验这一假设：1）通过微阵列分析鉴定影响TcR依赖性活化和生长的pro-IL-16调节基因，和2）确定pro-IL-16调节所选细胞周期相关基因的功能意义。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纳入个性化计划，以满足研究者的兴趣和技能，为培训医生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的潜力，以建立一个科学的利基，从学术生涯可以构建。

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.