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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.

项目总结/文摘