Molecular basis of recognition in the Immunological Synapse

免疫突触识别的分子基础

• 批准号: 10613479
• 负责人: Andras Fiser
• 金额: $ 54.6万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613479
• 关键词: Affinity; Antigen-Presenting Cells; Autoimmune Diseases; Binding; Binding Sites; Biochemical; Biological; Cell surface; Cells; Complex; Computational Technique; Disease; Engineering; Goals; Human; Immune response; Immunoglobulins; Immunotherapy; In Vitro; Libraries; Ligands; Malignant Neoplasms; Maps; Molecular; Natural Immunity; Phage Display; Pharmaceutical Preparations; Protein Engineering; Proteins; Proteome; Reagent; Regulation; Specificity; T-Lymphocyte; Techniques; Therapeutic; Validation; adaptive immunity; design; experimental study; extracellular; follow-up; immune function; immunological synapse; immunoregulation; insight; interdisciplinary approach; knowledgebase; mutant; novel; novel therapeutics; pharmacophore; receptor; synaptic function

Abstract Secreted and cell-surface-localized Immunoglobulin Superfamily proteins (‘extracellular IgSFs’) are important class of proteins, which includes proven targets for the treatment of autoimmune diseases and cancer. The human proteome contains ~500 extracellular IgSFs, the largest superfamily of cell surface molecules that contribute to the regulation of innate and adaptive immunity, via specific IgSF:IgSF interactions at the ‘Immune Synapse” formed between antigen-presenting cells and T-cells. Our long-term goal is to understand the molecular basis of interactions in the immune synapse. This requires the mapping of receptor-ligand interactions among the vast number of un-annotated IgSFs, and to gain insight about the specificity of these interactions. Subsequently, we plan to leverage our newly-gained insights into redesigning protein interfaces for specificity, both in order to generate new reagents that in turn can further interrogate the regulatory mechanisms within the immune synapse, and to establish potential new drug leads that can rationally modulate the immune response in diseases. In this application we will further develop our protein design-aided pharmacophore approach, ProtLID and utilize it for identifying cognate partners in the immune synapse, and for designing specific interfaces. We will also explore to synergisticly combine computational and experimental protein engineering techniques. We will develop an interdisciplinary approach where computationally designed, residue-based pharmacophore descriptions of the receptor-ligand interface are used to direct the library design in subsequent phage display experiments, allowing for the effective exploration of engineered constructs. All our computational results will be followed up with in vitro biochemical and cell-based experimental validation. These studies will directly expand the current knowledgebase of receptor-ligand pairs in the immune synapse and yield mutant molecules, with altered affinities and selectivities for therapeutic applications.

摘要 分泌的和细胞表面定位的免疫球蛋白超家族蛋白（“细胞外IgSF”）是 这是一类重要的蛋白质，其中包括用于治疗自身免疫性疾病和癌症的已证实的靶标。 人类蛋白质组包含约500个细胞外IgSF，这是细胞表面分子的最大超家族， 通过特异性IgSF：IgSF在“免疫”位点的相互作用，有助于调节先天性和适应性免疫。 在抗原呈递细胞和T细胞之间形成“突触”。 我们的长期目标是了解免疫突触中相互作用的分子基础。这 需要在大量未注释的IgSF中绘制受体-配体相互作用的图谱，并获得 了解这些相互作用的特殊性。随后，我们计划利用我们新获得的见解， 重新设计蛋白质界面的特异性，两者都是为了产生新的试剂，反过来又可以进一步 询问免疫突触内的调节机制，并建立潜在的新药线索 可以合理调节疾病中的免疫反应。 在这个应用中，我们将进一步发展我们的蛋白质设计辅助药效团方法，ProtLID 并利用它来识别免疫突触中的同源配偶体，以及设计特定的界面。我们 也将探索协同联合收割机结合计算和实验蛋白质工程技术。我们 将开发一种跨学科的方法，其中计算设计，基于残基的药效团 受体-配体界面的描述用于指导随后噬菌体展示中的文库设计 实验，允许工程构建的有效探索。我们所有的计算结果将 随后进行体外生物化学和基于细胞的实验验证。 这些研究将直接扩展免疫系统中受体-配体对的现有知识基础。 突触并产生突变分子，具有改变的亲和力和选择性用于治疗应用。