Regulation of non-canonical NF-kb signaling

描述(申请人提供)：本提案旨在为年轻内科科学家的科学和医学培训提供环境。作为培训的一部分，学生将完成医学博士学位和博士学位，在他的博士学位期间，特别强调自身免疫和增殖性免疫细胞疾病的发展。作为PHD的一部分，培训的重点将是研究非典型的核因子-kB途径的基本生化和分子调控。这种信号通路在自身免疫性疾病，如狼疮和类风湿性关节炎，以及增殖性免疫细胞疾病，如多发性骨髓瘤和淋巴瘤中似乎过度活跃。尽管这一途径的失调似乎与几种重要的血液疾病有关，但人们对该途径的正常调控知之甚少。这位学生已经发现了这一途径的组成部分之间以前未被认识到的相互作用，这可能在该途径的调节中发挥重要作用。这一提议旨在充分理解这种新的相互作用的生化基础和功能意义。加强对非规范的核因子-kB信号如何调控的了解，将有助于更好地理解这一途径所起作用的病理机制，如狼疮和多发性骨髓瘤。事实上，非规范的核因子-kB调控的新方面的缺陷最终可能被发现是某些患者疾病发展的根源。此外，对非规范信号如何调控的细微理解可能会为疾病治疗中该途径的药物操纵提供新的靶点。虽然这里描述的实验是高度生化的，但它们将提供一个智力和技术基础，供学生在以后的转化医学生涯中使用。事实上，作为该提案的最终目标的一部分，该学生将接受作为内科科学家职业生涯的临床方面的培训。这将通过参加医学院临床年的课程来实现。因此，这项提议的目的是让一名年轻的学生为成为内科科学家做好准备，并作为培训的一部分，解决血液病理学领域的重要科学问题。

DESCRIPTION (provided by applicant): This proposal aims to provide an environment for the scientific and medical training of a young physician- scientist. As part of the training the student will complete both MD and PhD degrees, with a specific scientific emphasis during his PhD on the development of autoimmune and proliferative immune cell disorders. Training as part of the PhD will be focused on investigating the basic biochemical and molecular regulation of the non-canonical NF-kB pathway. This signaling pathway appears to be hyperactive in autoimmune diseases such as lupus and rheumatoid arthritis as well as proliferative immune cell disorders such as multiple myeloma and lymphoma. Although dysregulation of this pathway seems to contribute to several important blood disorders, how the pathway is normally regulated is poorly understood. The student has identified a previously unappreciated interaction between components of this pathway which may play an important role in the pathway's regulation. This proposal aims to fully understand the biochemical basis and functional significance of this novel interaction. Enhanced knowledge of how non-canonical NF-kB signaling is regulated will allow for an improved understanding of the pathologies, such as lupus and multiple myeloma, in which this pathway plays a role. Indeed, defects in new aspects of non-canonical NF-kB regulation may ultimately be found to be the source of disease development in certain patients. Furthermore, nuanced understanding of how non-canonical signaling is regulated may allow for novel targets for pharmaceutical manipulation of the pathway in disease treatment. Although the experiments described here are highly biochemical they will provide an intellectual and technical foundation to be used in the student's later career in translational medicine. Indeed, as part of the final aim of the proposal, the student will be trained for the clinical aspect of his career as a physician scientist. This will be achieved through participation in the clinical years of the medical school curriculum. This proposal, then, aims to prepare a young student for a career as a physician scientist, and as part of the training addresses important scientific questions in the area of blood pathology.