High capacity protein purification for structural immunology

用于结构免疫学的高容量蛋白质纯化

• 批准号: 9309415
• 负责人: Brian M Baker
• 金额: $ 7.69万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309415
• 关键词: Affinity; Antigens; Award; Binding Proteins; Biophysics; CD3 Antigens; Cellular Immunity; Computational Technique; Data; Development; Health; Immune; Immune system; Immunity; Immunology; Immunotherapy; Knowledge; Learning; Major Histocompatibility Complex; Malignant Neoplasms; Modeling; Molecular; Motion; Outcome; Peptide/MHC Complex; Peptides; Property; Proteins; Request for Applications; Research; Research Personnel; Role; Shapes; Signal Transduction; Specificity; Structure; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Therapeutic; Translating; alpha-beta T-Cell Receptor; base; cell mediated immune response; computerized tools; cross reactivity; design; immunoregulation; improved; model design; molecular recognition; protein purification; rapid growth; structural biology; success

 DESCRIPTION (provided by applicant): αβ T cell receptor (TCR) recognition of peptide antigens presented by major histocompatibility complex proteins (pMHC) is a cornerstone of cellular immunity, defining specificity and initiating the signaling that leads to T cell-mediated immune responses. Although data for TCR-pMHC interactions has increased significantly over the past decade, we still have a poor understanding of how T cells and TCRs achieve their extraordinary recognition properties. Nonetheless, there continues to be rapid growth in the use of TCRs and T cell epitopes for immunotherapy, particularly for cancer. While there have been immunotherapy successes, there have also been complications and setbacks. It is widely accepted that an improved understanding of TCR/T cell recognition is needed for such therapies to reach their potential. This proposal describes an ambitious, tightly integrated study that blends protein biophysics, structural biology, computation, and immunology to understand TCR recognition, signaling, and immune modulation. It also describes the development of general strategies for designing and improving immune-based therapeutics by incorporating advances in TCR recognition into efforts in computational design and modeling, and vice versa. Priorities include 1) determining how TCR-pMHC binding is shaped by evolutionary and non-evolutionary forces; 2) understanding the varied mechanisms underlying specificity and cross-reactivity in T cell recognition; 3) determining the role of molecular motion in TCR triggering, including the structural and dynamical properties of intact TCR/CD3 complexes; 4) learning how to design TCRs with improved molecular recognition properties, emphasizing antigen specificity and the ability to carefully modulate rather than simply enhance affinity; 5) developing computational techniques for high throughput modeling of TCR cross-reactivity and the structural/dynamical properties of neo-antigens in MHC proteins; and 6) learning how peptides alter MHC properties beyond those ascertainable from static structures and how this modulation impacts cellular immunity.

 描述（由适用提供）：由主要的组织相容性复合蛋白（PMHC）提出的αβT细胞受体（TCR）识别肽抗原是细胞免疫共同体的基石，定义了特异性并启动信号传导，从而导致T细胞介导的免疫剂。尽管在过去的十年中，TCR-PMHC相互作用的数据显着增加，但我们仍然对T细胞和TCR如何获得其非凡识别特性有很差的了解。尽管如此，在免疫疗法中，尤其是用于癌症的TCR和T细胞表位的使用持续增长。尽管取得了免疫疗法的成功，但也存在并发症和挫折。人们普遍认为，需要提高对TCR/T细胞识别的理解，以使这种疗法发挥其潜力。该建议描述了一项雄心勃勃的紧密整合研究，该研究将蛋白质生物物理学，结构生物学，计算和免疫学融合在一起，以了解TCR识别，信号传导和免疫调节。它还通过将TCR识别的进步转化为计算设计和建模的努力，反之亦然，以开发设计和改善基于免疫的治疗剂的一般策略，反之亦然。优先级包括1）确定TCR-PMHC结合是如何通过进化和非进化力来塑造的； 2）了解T细胞识别中特异性和交叉反应性的不同机制； 3）确定分子运动在TCR触发中的作用，包括完整TCR/CD3复合物的结构和动态特性； 4）学习如何以改进的分子识别特性设计TCR，强调抗原特异性和仔细调节而不是简单地增强亲和力的能力； 5）开发用于TCR交叉反应性高吞吐量建模的计算技术以及MHC蛋白中新抗原的结构/动力学特性； 6）学习Pepperides如何改变MHC的性质超出静态结构可确定的特性，以及该调节如何影响细胞免疫组织化学。