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

线性泛素结合蛋白对炎症细胞因子产生的调节控制

基本信息

批准号：
10337076
负责人：
Alexander Gitlin
金额：
$ 7.69万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-02 至 2022-07-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337076
关键词：
Academia Advisory Committees Affect Anti-Inflammatory Agents Apoptosis Apoptotic Autoimmune Diseases Autoimmunity Binding Binding Proteins Biological Process Biological Response Modifiers Biology CASP8 gene CRISPR/Cas technology CSF3 gene Cell Death Chronic Disease Clinical Pathology Clinics and Hospitals Communicable Diseases Complex Core Facility Dendritic Cells Disease Doctor of Medicine Doctor of Philosophy Environment Equilibrium Five-Year Plans Gene Deletion Genes Genetic Genetic Polymorphism Health Homeostasis Human IRAK1 gene IRAK4 gene Immune Immune System Diseases Immunity Immunodeficiency and Cancer Immunologic Receptors In Vitro Industry Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Innate Immune Response Innate Immune System Institution Interleukin-1 Receptors Interleukin-6 Joints Knock-in Knockout Mice Ligands Light Link MAP Kinase Gene Mediating Mentors Mentorship Modeling Molecular Mus NF-kappa B Natural Immunity Output Pathway interactions Pattern recognition receptor Physicians Point Mutation Polyubiquitin Post-Translational Protein Processing Production Proteins RIPK1 gene Receptor Signaling Regulation Research Research Personnel Research Proposals Residencies Resistance Resources Ribonucleases Role Scientist Series Severities Signal Pathway Signal Transduction Syndrome System TLR1 gene TLR3 gene TLR4 gene TLR7 gene TNF gene TNFRSF5 gene Testing Therapeutic Time Toll-like receptors Training Tumor Necrosis Factor Receptor Ubiquitin Ubiquitination Universities autoinflammatory career career development cell type cytokine disease-causing mutation experimental study in vivo inhibitor laboratory facility macrophage medical schools mouse model mutant mutant mouse model novel novel strategies programs receptor recruit response

项目摘要

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.

项目概要/摘要该提案概述了 PI 亚历山大·吉特林 (Alexander Gitlin) 博士的五年计划，旨在帮助他为独立研究做好准备吉特林博士作为一名医师科学家获得了威尔医学博士/博士学位。康奈尔大学/洛克菲勒大学/斯隆凯特琳三机构医学博士-博士项目，目前正在完成住院医师培训。斯坦福医院和诊所的临床病理学在住院期间，吉特林博士开发了联合指导的方法。该研究项目由 Bali Pulendran 博士（斯坦福大学）和 Vishva Dixit（基因泰克公司）共同指导。 Pulendran 博士和 Dixit 博士是长期的同事和合作者，专业知识高度互补。 Pulendran 是 Toll 样受体、先天免疫和树突状细胞方面的专家。 Pulendran 博士和 Dixit 博士都担任过炎症信号、细胞死亡和泛素生物学的导师。为众多学员提供了帮助，其中许多人已成为学术界或工业界的主要研究人员。导师计划使吉特林博士能够充分利用两所大学的综合资源和专业知识邻近的世界一流研究机构斯坦福大学和基因泰克将提供为吉特林博士发展自己的独立科学事业提供了良好的环境。组建了一个 K08 咨询委员会，由高级研究人员组成，他们的科学专业知识和他们的指导将极大地帮助吉特林博士的职业发展，他们包括斯蒂芬·加利博士、丹尼斯·莫纳克博士、此外，吉特林博士将有机会参加课程作业、静修、研讨会和培训。通过斯坦福大学医学院、斯坦福博士后事务办公室和最后，吉特林博士可用的科学资源包括：斯坦福大学和基因泰克的 Pulendran/Dixit 实验室和核心设施，代表了本文详述的研究计划旨在揭示分子的本质。线性泛素控制先天免疫反应程度的机制。炎症和细胞因子反应是多种慢性疾病的基本特征，包括自身免疫、自身炎症综合征、传染病、免疫缺陷和癌症。调节炎症信号传导的复杂信号传导途径仍在机制上被阐明在吉特林博士担任迪克西特博士和普伦德兰博士的短暂指导期间，他发现 NEDD4 结合蛋白 1 (N4BP1) 是一种线性泛素结合蛋白，是 Toll 样受体的新型调节剂 (TLR) 反应在目标 1 中，我们将检验 N4BP1 差异调节炎症细胞因子的假设。在目标 2 中，我们将通过以下方式剖析 N4BP1 活性的机制基础。我们预计这些研究将阐明一种新的途径。一种以前神秘的线性泛素结合蛋白选择性地控制 TLR 的细胞因子输出。学习为吉特林博士完成培训并开展独立职业生涯提供了极好的平台。