Regulatory control of inflammatory cytokine production by a linear ubiquitin-binding protein

项目摘要/摘要 这项提案为私人侦探亚历山大·吉特林博士勾勒出了一个五年计划，以帮助他为独立的 作为一名内科科学家的学术生涯。吉特林博士从威尔大学获得医学博士/博士学位 康奈尔/洛克菲勒/斯隆-凯特林三所学院医学博士课程，目前正在完成 斯坦福医院和诊所的临床病理学。在实习期间，吉特林博士开发了一种联合指导 研究计划，由Bali Pulendran博士(斯坦福大学)和Vishva Dixit博士(Genentech，Inc.)共同建议。 普伦德兰博士和迪克西特博士是长期的同事和合作者，专业知识互补性很强。Dr。 普伦德兰是Toll样受体、先天免疫和树突状细胞方面的专家；迪克西特博士是 炎症信号、细胞死亡和泛素生物学。Pulendran博士和Dixit博士都曾担任过导师 对许多受训者来说，其中许多人已经成为学术界或工业界的主要研究人员。这个关节 导师计划为吉特林博士提供了充分利用目前在两家公司的联合资源和专业知识 邻近的世界级研究机构，斯坦福大学和基因技术公司，将提供 为吉特林博士发展自己的独立科学事业提供了出色的环境。此外，吉特林博士 成立了一个K08咨询委员会，由高级调查人员组成，他们的科学专长和 导师制将极大地帮助吉特林博士的职业发展。其中包括斯蒂芬·加利博士、丹尼斯·莫纳克博士、 斯科特·博伊德和安德烈·肖。此外，吉特林博士将有机会参加课程作业、务虚会、研讨会和 通过斯坦福大学医学院、斯坦福博士后事务办公室和 基因泰克博士后项目。最后，吉特林博士可利用的科学资源包括 普伦德兰/迪克西特实验室和斯坦福大学和基因泰克的核心设施，代表着 一套非凡的科学资源。这里详述的研究提案试图揭示分子 线性泛素控制先天免疫反应的机制。监管不力 炎症和细胞因子反应是多种慢性病的基本特征，包括 自身免疫、自体炎症综合征、传染病、免疫缺陷和癌症。然而，许多人 调节炎症信号的复杂信号通路仍在以一种机械的方式被解开 水平。在吉特林博士作为Dixit博士和Pulendran博士共同导师的短暂时间里，他发现 NEDD4结合蛋白1(N4BP1)是一种新型的Toll样受体调节因子，是一种线性泛素结合蛋白 (TLR)响应。在目标1中，我们将检验N4BP1对炎性细胞因子的不同调控的假设 TLR信令下游生产。在目标2中，我们将通过以下方式剖析N4BP1活性的机制基础 使其独立的功能基序失活。我们预计这些研究将阐明一种新的途径，通过它 一个先前神秘的线性泛素结合蛋白选择性地控制TLRs的细胞因子输出。这些 研究为吉特林博士完成培训和开始他的独立职业生涯提供了一个极好的平台。

PROJECT SUMMARY/ABSTRACT This proposal outlines a five-year plan for the PI, Dr. Alexander Gitlin, to prepare him for an independent academic career as a physician-scientist. Dr. Gitlin received his M.D./Ph.D. degrees from the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional M.D.-Ph.D. program and is currently completing residency in Clinical Pathology at Stanford Hospital and Clinics. During residency, Dr. Gitlin developed a jointly mentored research program, co-advised by Drs. Bali Pulendran (Stanford University) and Vishva Dixit (Genentech, Inc.). Drs. Pulendran and Dixit are longtime colleagues and collaborators with highly complementary expertise. Dr. Pulendran is an expert in toll-like receptors, innate immunity, and dendritic cells; Dr. Dixit is an expert on inflammatory signaling, cell death, and ubiquitin biology. Both Drs. Pulendran and Dixit have served as mentors to numerous trainees, many of whom have become leading investigators in academia or industry. This joint mentorship program provides Dr. Gitlin with full access to the combined resources and expertise present at two neighboring, world-class research institutions, Stanford University and Genentech, which will provide outstanding environments for Dr. Gitlin to develop his own independent scientific career. In addition, Dr. Gitlin has assembled a K08 advisory committee composed of senior investigators whose scientific expertise and mentorship will greatly aid Dr. Gitlin’s career development. They include Drs. Stephen Galli, Denise Monack, Scott Boyd, and Andrey Shaw. Furthermore, Dr. Gitlin will have access to coursework, retreats, seminars and resources through Stanford University’s School of Medicine, The Stanford Office of Postdoctoral Affairs, and the Genentech Postdoctoral Program. Finally, the scientific resources available to Dr. Gitlin comprise the Pulendran/Dixit laboratories and core facilities at both Stanford University and Genentech, representing an extraordinary set of scientific resources. The research proposal detailed herein seeks to uncover the molecular mechanisms by which linear ubiquitin controls the magnitude of the innate immune response. Dysregulated inflammatory and cytokine responses are fundamental features of multiple chronic diseases, including autoimmunity, autoinflammatory syndromes, infectious diseases, immunodeficiencies and cancer. Yet, many of the complex signaling pathways that regulate inflammatory signaling are still being unraveled at a mechanistic level. During Dr. Gitlin’s short time as a co-mentee of Drs. Dixit and Pulendran, he has discovered that the NEDD4-binding protein 1 (N4BP1), a linear ubiquitin-binding protein, is a novel regulator of toll-like receptor (TLR) responses. In Aim 1, we will test the hypothesis that N4BP1 differentially regulates inflammatory cytokine production downstream of TLR signaling. In Aim 2, we will dissect the mechanistic basis of N4BP1 activity by inactivating its independent functional motifs. We anticipate these studies will elucidate a novel pathway by which a previously enigmatic linear ubiquitin-binding protein selectively controls the cytokine output of TLRs. These studies provide an excellent platform for Dr. Gitlin to complete his training and launch his independent career.