Atoms-to-Animals: Structural Genomics of Immunity

原子到动物：免疫结构基因组学

• 批准号: 7982794
• 负责人: STANLEY G NATHENSON
• 金额: $ 117.31万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982794
• 关键词: Amino Acid Sequence; Animal Disease Models; Animals; Autoimmune Diseases; Behavior; Biochemical; Biological Assay; Biological Process; Cell surface; Cells; Commit; Communicable Diseases; Evolution; Generations; Health; Human; Immune Targeting; Immune response; Immunity; Immunologist; In Vitro; Knock-in Mouse; Lead; Malignant Neoplasms; Natural Immunity; Property; Proteins; Reagent; Research Infrastructure; Resolution; Series; Shapes; Specificity; Structural Biologist; Structure; Structure-Activity Relationship; Therapeutic; Work; adaptive immunity; base; human disease; immune function; in vivo; insight; mouse model; mutant; novel; public health relevance; structural biology; structural genomics

DESCRIPTION (provided by applicant): The Immune Function Network (IFN), a consortium of immunologists, geneticists, computational biochemists, and high throughput structural biologists, is committed to the coordinated structural, in vitro biochemical and in vivo functional analyses of the secreted molecules and ectodomains of cell surface molecules that control adaptive and innate immunity. These molecules are validated targets for immune-based therapies to treat a wide range of autoimmune diseases, infectious diseases and cancers, and are indeed therapeutics in their own right. The IFN, subscribes to a series of underlying principles: 1) target selection supports hypothesis-driven structural biology by identifying unique primary amino acid sequence signatures that predict unique structural features, which are in turn responsible for unique biological function; 2) the high resolution structures of these molecules are exceptionally revealing as they inform on oligomeric state, valency, specificity and general architectural features, all of which are fundamental mechanistic contributors to immune function; 3) these structures can be readily exploited by biochemical and computational approaches to guide the generation of molecules with specifically altered biochemical and biophysical properties; 4) these "surgically-defined" mutants represent novel reagents that will lead to new mechanistic insights in in vitro cell-based assays and in vivo animal models of disease; 5) the molecules predicted to be most informative will guide the generation of knock-in mouse models to provide in vivo structure-function relationships for innate and adaptive immunity. This "Atoms-to-Animals" approach represents the next step in the evolution of Structural Biology as it maximally leverages structural information and provides a comprehensive and powerful paradigm for the study of normal, pathological, and therapeutic immune responses. PUBLIC HEALTH RELEVANCE: The proteins that control the immune response are fundamentally important for human health, as they protect against infectious diseases and cancer, and their aberrant behavior is responsible for a wide range of devastating autoimmune diseases. Understanding the shapes and structures of these molecules affords the opportunity to develop novel protein-based therapeutics to treat this entire spectrum of human diseases.

描述（由申请人提供）：免疫功能网络（IFN），免疫学家，遗传学家，计算生物化学家和高吞吐量结构生物学家的联盟，致力于协调的结构，体外生物化学和体内和体内的秘密分子和构造分子的体内功能分析。这些分子是基于免疫疗法的验证靶标，可治疗多种自身免疫性疾病，传染病和癌症，并且本身就是治疗疗法。 IFN订阅一系列基本原则：1）目标选择通过识别预测独特的结构特征的独特的原代氨基酸序列特征来支持假设驱动的结构生物学，这反过来又负责独特的生物学功能； 2）这些分子的高分辨率结构在寡聚状态，价值，特异性和一般体系结构特征的信息时，都非常揭示，所有这些结构都是对免疫功能的基本机械贡献者； 3）这些结构可以通过生化和计算很容易利用 指导分子具有特异性改变的生化和生物物理特性的方法； 4）这些“手术定义”的突变体代表了新型试剂，这些试剂将导致基于体外细胞的分析和体内动物模型的新机械见解； 5）预测最有用的分子将指导敲入小鼠模型的产生，以提供体内结构功能 - 与先天和适应性免疫的关系。这种“原子对动物”方法代表了结构生物学演变的下一步，因为它可以最大程度地利用结构信息，并为研究正常，病理和治疗性免疫反应提供了全面而强大的范式。 公共卫生相关性：控制免疫反应的蛋白质对人类健康至关重要，因为它们可以防止传染病和癌症，并且它们的异常行为造成了多种毁灭性的自身免疫性疾病。了解这些分子的形状和结构为开发基于蛋白质的新型治疗剂以治疗整个人类疾病的机会。