Structural and Mechanistic Elucidation of NAIP/NLRC4 Inflammasomes in Innate Immunity

先天免疫中 NAIP/NLRC4 炎症小体的结构和机制阐明

基本信息

批准号：
10078244
负责人：
Liman Zhang
金额：
$ 24.84万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078244
关键词：
3-Dimensional Achievement Address Award BIR Domain Bacteria Bacterial Infections Biochemical CASP1 gene Caspase Cell Death Cells Cellular biology Colitis associated colorectal cancer Complex Cryoelectron Microscopy Data Development Development Plans Diabetes Mellitus Disease Educational workshop Environment Family Flagellin Gingivitis Goals Gout Gram-Negative Bacteria Host Defense Human Immune response Immune system Immunologist Immunology Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-1 beta Interleukin-18 International Knowledge Lead Learning Legionella pneumophila Legionnaires&apos Disease Ligands Link Macrophage activation syndrome Malignant Neoplasms Mediating Medical center Mentors Mentorship Metabolic Diseases Modeling Molecular Molecular Conformation Molecular Medicine Mus Mutation Mutation Analysis N-terminal Natural Immunity Needles Non-Insulin-Dependent Diabetes Mellitus Parkinson Disease Pathogenicity Pattern Periodontitis Play Process Production Proteins Pseudomonas Psoriasis Publishing Regulation Research Rod Role Sagittaria Salmonella Salmonella typhimurium Science Series Signal Transduction Specificity Structure System Techniques Testing Training Training Programs Type III Secretion System Pathway Work autoinflammation base career career development conformational conversion cytokine dalton drug development insight medical schools mouse model nanoscale novel therapeutic intervention pathogen polymerization programs protein complex receptor reconstitution reconstruction recruit screening small molecule small molecule inhibitor structural biology symposium therapy development tumorigenesis

项目摘要

Background: The NAIP/NLRC4 inflammasomes are defenders against cytosolic infections by bacteria such as Salmonella and Pseudomonas through recruitment and activation of pro-caspase-1, lead to the production of interleukin-1β (pro-IL-1β) and IL-18, and induces pyroptotic cell death. The NAIP/NLRC4 inflammasomes are comprised with three components, the bacterial ligands such as flagellin, the NAIPs, and the NLRC4 protein. NAIPs recognize different bacterial ligands and determine the specificity of NAIP/NLRC4 inflammasomes. Abnormal inhibition and activation of these complexes cause human inflammatory diseases, NLRC4 mutation also related with the colitis-associated colorectal cancer (CAC). This project on structural and biochemical studies of the NAIP/NLRC4 inflammasomes will provide important insights into cytosolic bacteria sensing mechanisms and lead to new strategies on disease treatment and drug development. Research/Career Goals: My short-term goal is to understand the structural basis of how NAIP/NLRC4 inflammasome are activated by bacterial ligand, and the long-term goal is to understand the complicated immune responses upon pathogen infection. The specific aims of this project are to elucidate the mechanism of ligand recognition by NAIP and NLRC4, the autoinhibited conformation of NAIP, and to identify small molecule inhibitors of CARD-CARD interactions in inflammasomes. Research/Career Development Plan and Environment: I will take cryo-EM workshops at Harvard Medical School (HMS) and Center for Nanoscale Systems (CNS), learn cell biology and small molecule screening techniques from the mentor's lab, and complete the proposed study. I will attend a series of international conferences to expand my knowledge in immunology. Under the mentorships of Drs. Hao Wu (BCH), Maofu Liao (HMS) and Timothy J. Mitchison (HMS), I will follow the traditional training program to maximize my professional abilities for transition into independence. Program in Cellular and Molecular Medicine (PCMM) at BCH and HMS will provide me with the great environment for scientific achievement and career development to become an independent structural immunologist during this award.

背景：NAIP/NLRC4炎症体是防御细菌胞质感染的捍卫者通过募集和激活pro-Caspase-1的沙门氏菌和假单胞菌，导致产生白介素-1β（Pro-IL-1β）和IL-18，并诱导凋亡细胞死亡。 NAIP/NLRC4炎症体是由三个成分组成，包括鞭毛蛋白，NAIP和NLRC4蛋白等细菌配体。 NAIP识别不同的细菌配体，并确定NAIP/NLRC4炎症体的特异性。这些复合物的异常抑制和激活会导致人类炎症性疾病，NLRC4突变也与结肠炎相关的结直肠癌（CAC）有关。这个关于结构和生化的项目 NAIP/NLRC4炎症体的研究将为胞质细菌传感器提供重要的见解机制并导致有关疾病治疗和药物发展的新策略。研究/职业目标：我的短期目标是了解NAIP/NLRC4的结构性基础炎性体被细菌配体激活，长期目标是了解复杂的病原体感染的免疫反应。该项目的具体目的是阐明机制 NAIP和NLRC4的配体识别，自身抑制了NAIP的构象，并鉴定炎症中卡卡相互作用的分子抑制剂。研究/职业发展计划和环境：我将在哈佛医疗学校（HMS）和纳米级系统中心（CNS），学习细胞生物学和小分子筛查精神实验室的技术，并完成拟议的研究。我将参加一系列国际会议扩大我在免疫学方面的知识。在Drs的概念下。 Hao Wu（BCH），MAOFU LIAO（HMS）和Timothy J. Mitchison（HMS），我将遵循传统培训计划，以最大化我的过渡到独立的专业能力。在细胞和分子医学（PCMM）方面的程序 BCH和HMS将为我提供科学成就和职业发展的伟大环境在该奖项期间成为独立的结构免疫学家。