Atoms-to-Animals: Structural Genomics of Immunity

描述(申请人提供)：免疫功能网络(IFN)是一个由免疫学家、遗传学家、计算生物化学家和高通量结构生物学家组成的联盟，致力于对控制适应性和先天免疫的细胞表面分子的分泌分子和胞外区进行协调的结构、体外生化和体内功能分析。这些分子是以免疫为基础的疗法的有效靶点，用于治疗广泛的自身免疫性疾病、传染病和癌症，而且它们本身确实是治疗方法。干扰素遵循一系列基本原则：1)靶标选择支持假说驱动的结构生物学，通过识别预测独特结构特征的独特初级氨基酸序列签名，这些特征反过来又负责独特的生物功能；2)这些分子的高分辨率结构特别揭示，因为它们信息低聚状态、价态、特异性和一般结构特征，所有这些都是免疫功能的基本机制贡献者；3)这些结构可以很容易地被生化和计算利用 4)这些“手术定义的”突变体代表了新的试剂，将导致对体外细胞分析和体内疾病动物模型的新的机制的深入了解；5)预测信息最丰富的分子将指导敲入小鼠模型的产生，以提供体内结构与功能的关系，以实现先天免疫和获得性免疫。这种“原子到动物”的方法代表了结构生物学进化的下一步，因为它最大限度地利用了结构信息，并为研究正常、病理和治疗性免疫反应提供了一个全面而强大的范例。 与公共健康相关：控制免疫反应的蛋白质对人类健康至关重要，因为它们可以预防传染病和癌症，它们的异常行为导致了一系列破坏性的自身免疫性疾病。了解这些分子的形状和结构为开发新的基于蛋白质的疗法来治疗这一整个人类疾病谱提供了机会。

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.