Dissecting inflammasome anatomy: mechanistic studies and potential intervention

解剖炎症体解剖：机制研究和潜在干预

• 批准号: 8618504
• 负责人: Qian Yin
• 金额: $ 11.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618504
• 关键词: Acute; Adaptor Signaling Protein; Anatomy; Area; Award; Behavior; Biochemical; Biological; Biological Assay; Biology; Boston; Caspase-1; Cell Death; Cells; Chronic Disease; Communities; Complex; Consult; Coupled; Data; Development; Diabetes Mellitus; Disease; Educational workshop; Electron Microscopy; Filament; Future; Goals; Gout; Human; Hydrocarbons; Hydrogen Bonding; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inherited; Insecta; Interleukin-1; Interleukin-18; Intervention; Invaded; Lead; Learning; Malignant Neoplasms; Mammalian Cell; Medical; Membrane Proteins; Mentors; Metabolic Diseases; Mus; Mutation; Names; Nature; Nucleotides; Organism; Pathway interactions; Pediatric Hospitals; Peptides; Pharmaceutical Preparations; Phase; Positioning Attribute; Process; Protein Engineering; Proteins; Psoriasis; Reaction; Regulation; Research; Resolution; Resources; Sepsis; Signal Transduction; Small Molecule Chemical Library; Solubility; Stress; Structural Biologist; Structure; Surface; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Work; X-Ray Crystallography; Yin; base; biophysical techniques; cell type; cytokine; drug development; high throughput screening; inhibitor/antagonist; interfacial; medical schools; microbial; mouse model; pathogen; procaspase-1; protein complex; public health relevance; receptor; reconstitution; reconstruction; repaired; screening; skills; small molecule; small molecule libraries; therapeutic development; therapeutic target; tool

DESCRIPTION (provided by applicant): The principal aim of this proposal is to elucidate the structures and activation and regulation mechanisms of the multi-protein complex inflammasomes, and to develop tool compounds that perturb the assembly of the inflammasomes with potentials for future therapeutic interventions. Dr. Qian Yin is currently a research fellow in Boston Children's Hospital and Harvard Medical School with an immediate goal of completing one-year mentored research before establishing herself in a tenure-track academic position. Dr. Yin's long-term goals include independent researches to understand human innate immune and inflammatory systems and their interaction with pathogens and environmental and intrinsic stresses, with the hope of finding amenable therapeutic targets and effective means for immune and inflammatory diseases. Dr. Yin is a well-trained structural biologist specialized in innate immune and inflammatory signaling. The project will be conducted at Boston Children's Hospital in the rich research community of Longwood Medical Area of Boston, with all facilities and resources from neighboring Harvard Medical School available to the candidate. Dr. Yin will be mentored by Dr. Hao Wu in structural and biophysical approaches to elucidate inflammasome structures and co-mentored by Dr. Timothy Mitchison in development of high throughput assays and tool compounds. During the one-year mentored period, Dr. Yin will learn new techniques such as electron microscopy and high throughput screening under the guidance of the mentors, and develop professional skills by attending classes, seminars, and workshops. After that Dr. Yin plans to make the transition to independence with the assistance of the proposed awards. Inflammasomes are multi-protein complexes that launch the first-line inflammatory responses. During the mentored phase Dr. Yin proposes to reconstruct high-resolution electron microscopy (EM) structure of the AIM2 inflammasome, with X-ray crystallography providing detailed interfacial interactions (Aim 1). This period will also see Dr. Yin clarify the working mechanism of p202, a natural AIM2 inflammasome inhibitor. The proposed work builds heavily on the preliminary EM data of in vitro reconstitution of ASC PYD domain, a common adaptor in most inflammasomes. For the independent phase, Dr. Yin will 1) investigate the assembly mechanisms of NLRP3 inflammasome and elucidate the differential requirements among various inflammasomes (Aim 2), and 2) assay structure-based stabilized helical peptides and screen chemical libraries for small molecules that can perturb inflammasome assembly, in the hope to find druggable interfaces and tool compounds with potential therapeutic values (Aim 3). RELEVANCE: Inflammation is a self-protection process that needs to be tightly regulated. Understanding inflammasome activation and regulation will provide new avenues for treatment of many metabolic diseases, e.g. diabetes and various cancers, as well as hereditary autoinflammatory diseases.

描述（由申请人提供）：该提案的主要目的是阐明多蛋白质复合物炎症体的结构，激活和调节机制，并开发出扰动炎性症的工具化合物，并带有潜在的未来治疗干预措施。 Qian Yin博士目前是波士顿儿童医院和哈佛医学院的一名研究员，其直接目标是完成一年的指导研究，然后才能确立自己的终身学术职位。 Yin博士的长期目标包括独立的研究，以了解人类先天免疫和炎症系统，以及它们与病原体以及环境和内在压力的相互作用，希望找到可正常的治疗靶标和免疫和炎症性疾病的有效手段。 Yin博士是一位训练有素的结构生物学家，专门从事先天免疫和炎症信号传导。该项目将在波士顿朗伍德医疗区丰富的研究社区的波士顿儿童医院进行，候选人提供了邻近哈佛医学院的所有设施和资源。 Yin博士将由Hao Wu博士指导的结构和生物物理方法，以阐明炎症体结构，并由Timothy Mitchison博士在开发高吞吐量测定和工具化合物方面进行。在为期一年的指导期内，Yin博士将在导师的指导下学习新技术，例如电子显微镜和高吞吐量筛查，并通过参加课程，研讨会和讲习班来发展专业技能。之后，Yin博士计划在拟议奖项的协助下过渡到独立。炎症是发射一线炎症反应的多蛋白质复合物。在指导阶段，Yin博士提议重建AIM2炎症体的高分辨率电子显微镜（EM）结构，X射线晶体学提供了详细的界面相互作用（AIM 1）。这一时期还将看到Yin博士阐明P202的工作机理，P202是一种自然的AIM2炎症体抑制剂。拟议的工作在大多数炎症中的常见适配器ASC PYD域的体外重构的初步数据基础上建立在很大程度上。对于独立阶段，Yin博士将1）研究NLRP3炎性体的组装机制，并阐明各种炎症体之间的差异需求（AIM 2）和2）基于结构的稳定螺旋肽和筛选化学库的小分子的化学库，这些小分子可以促进炎症组组装的小分子，以构成势力型的互动工具，以构成型号的互动工具和工具，并构成了3个势力。 相关性：炎症是一个自我保护过程，需要严格调节。 了解炎性体激活和调节将为许多代谢疾病的治疗提供新的途径，例如糖尿病和各种癌症以及遗传性自身炎症疾病。