Regulation of non-canonical NF-kb signaling

描述（由申请人提供）：本提案旨在为年轻医师-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和博士学位，在他的博士学位期间，将特别强调自身免疫和增殖性免疫细胞疾病的发展。作为博士学位的一部分，培训将侧重于研究非典型NF-kB途径的基本生化和分子调控。这一信号通路在自身免疫性疾病如狼疮和类风湿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显得异常活跃。尽管这一通路的失调似乎导致了几种重要的血液疾病，但人们对这一通路的正常调节机制知之甚少。该学生已经确定了该途径的组成部分之间以前未被重视的相互作用，这可能在该途径的调节中发挥重要作用。本提案旨在充分了解这种新型相互作用的生化基础和功能意义。加强对非规范NF-kB信号如何调节的了解，将有助于更好地理解这种途径发挥作用的病理，如狼疮和多发性骨髓瘤。事实上，在非规范NF-kB调控的新方面的缺陷可能最终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致理解可能会为疾病治疗中药物操纵该途径提供新的靶点。虽然这里描述的实验是高度生化的，但它们将为学生以后在转化医学领域的职业生涯提供智力和技术基础。事实上，作为该提案最终目标的一部分，该学生将作为一名内科科学家接受临床方面的培训。这将通过参加医学院临床课程来实现。因此，该提案旨在为年轻学生作为医生科学家的职业做好准备，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.