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

• 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
• 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

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.

项目摘要/摘要 该提案概述了PI的五年计划，亚历山大吉特林博士，为他独立做准备。 作为一名物理学家和科学家的学术生涯。Gitlin博士获得了医学博士学位/博士从韦尔度 康奈尔/洛克菲勒/斯隆-凯特琳三机构医学博士-博士计划，目前正在完成居住在 斯坦福大学医院临床病理学。在住院期间，Gitlin博士开发了一种联合指导的 Bali Pulendran博士（斯坦福大学）和Vishva Diplomat博士（Genentech，Inc.）共同担任顾问。 Drs. Pulendran和Diplomat是长期的同事和合作者，具有高度互补的专业知识。博士 Pulendran博士是Toll样受体、先天免疫和树突细胞方面的专家; 炎症信号传导、细胞死亡和泛素生物学。Pulendran博士和Diplomat博士都曾担任过导师 许多受训人员，其中许多人已成为学术界或工业界的主要调查人员。这一联合 导师计划为Gitlin博士提供了充分的资源和专业知识，目前在两个 邻近的世界级研究机构，斯坦福大学和基因泰克，这将提供 Gitlin博士发展自己独立的科学事业的良好环境。此外，Gitlin博士 已经组建了一个K 08咨询委员会，由高级研究人员组成，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。他们包括斯蒂芬·加利博士，丹尼斯·莫纳克， 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，务虚会，研讨会和 通过斯坦福大学医学院，斯坦福大学博士后事务办公室和 Genentech博士后项目。最后，Gitlin博士可用的科学资源包括： Pulendran/Diplomat实验室和斯坦福大学和基因泰克的核心设施，代表了 非凡的科学资源。本文详细介绍的研究提案旨在揭示分子 线性泛素控制先天免疫应答的大小的机制。失调 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、自身炎性综合征、感染性疾病、免疫缺陷和癌症。然而，许多 调节炎症信号的复杂信号传导途径仍在以一种机制被解开， 水平在吉特林博士作为Diplomat博士和Pulendran博士的共同指导者的短暂时间内，他发现， NEDD 4结合蛋白1（N4 BP 1）是一种线性泛素结合蛋白，是Toll样受体的新型调节因子 (TLR)应答在目标1中，我们将检验N4 BP 1差异调节炎性细胞因子的假设 TLR信号传导的下游生产。在目标2中，我们将通过以下方式剖析N4 BP 1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， 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。这些 研究为Gitlin博士完成培训并开始独立职业生涯提供了一个很好的平台。