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

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

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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.

项目摘要/摘要该提案概述了PI的五年计划Alexander Gitlin博士，为他准备独立作为身体科学家的学术生涯。吉特林博士获得了医学博士/ph.D。威尔的学位 Cornell/Rockefeller/Sloan-Kettering Tri-Institureal M.D.-Ph.D.计划，目前正在完成斯坦福医院和诊所的临床病理学。居住期间，吉特林博士共同推荐了研究计划，由Drs共同设计。 Bali Pulendran（斯坦福大学）和Vishva Dixit（Genentech，Inc。）。博士。 Pulendran和Dixit是长期的同事和具有高度完善专业知识的合作者。博士 Pulendran是Toll样受体，先天免疫和树突状细胞的专家。 Dixit博士是专家炎症信号传导，细胞死亡和泛素生物学。两个博士。 Pulendran和Dixit曾担任导师对于众多学员来说，其中许多人已成为学术界或行业的主要研究人员。这个关节 Menorship Program为Gitlin博士提供了完全访问两个的合并资源和专业知识邻近，世界一流的研究机构，斯坦福大学和Genentech，将提供吉特林博士培养自己的独立科学生涯的杰出环境。此外，吉特林博士已经组建了一个由高级调查员组成的K08咨询委员会，其科学专业知识和 Menorship将极大地帮助Gitlin博士的职业发展。他们包括Drs。斯蒂芬·加利（Stephen Galli），丹妮丝·莫纳克（Denise Monack），斯科特·博伊德（Scott Boyd）和安德烈·肖（Andrey Shaw）。此外，吉特林博士将可以访问课程，务虚会，半手和通过斯坦福大学医学院，斯坦福大学的博士后办公室和 Genentech博士后计划。最后，吉特林博士可用的科学资源建立了 Stanford University和Genentech的Pulendran/Dixit实验室和核心设施，代表非凡的科学资源集。本文详细介绍的研究建议旨在揭示分子线性泛素控制先天免疫反应的大小的机制。失调炎症性和细胞因子反应是多种慢性疾病的基本特征，包括自身免疫性，自身炎症综合征，传染病，免疫缺陷和癌症。但是，很多调节炎症信号传导的复杂信号通路仍在机械上揭示等级。在吉特林博士（Gitlin）担任Drs的共同体的短时间内。 Dixit和Pulendran，他发现 NEDD4结合蛋白1（N4BP1）是一种线性泛素结合蛋白，是一种新型的Toll样受体调节剂（TLR）响应。在AIM 1中，我们将检验以下假设：N4BP1对炎症细胞因子进行不同的调节 TLR信号下游的生产。在AIM 2中，我们将通过灭活其独立的功能基序。我们预计这些研究将阐明一种新的途径先前神秘的线性泛素结合蛋白选择性控制TLR的细胞因子输出。这些研究为吉特林博士提供了一个绝佳的平台，可以完成他的培训并启动他的独立职业。