Molecular basis of recognition in the Immunological Synapse

免疫突触识别的分子基础

• 批准号: 10386851
• 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/10386851
• 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; Molecular; Natural Immunity; Phage Display; Pharmaceutical Preparations; Protein Engineering; Proteins; Proteome; Reagent; Regulation; Specificity; T-Lymphocyte; Techniques; Therapeutic; Validation; adaptive immunity; base; design; experimental study; extracellular; follow-up; immune function; immunological synapse; 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.

抽象的 分泌型和细胞表面定位的免疫球蛋白超家族蛋白（“细胞外 IgSF”） 重要的一类蛋白质，其中包括已被证实的治疗自身免疫性疾病和癌症的靶标。 人类蛋白质组包含约 500 个细胞外 IgSF，这是最大的细胞表面分子超家族， 通过特定的 IgSF:IgSF 在“免疫”的相互作用，有助于调节先天性和适应性免疫 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相互作用的分子基础。 需要绘制大量未注释的 IgSF 之间的受体-配体相互作用图谱，并获得 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以获得特异性，两者都是为了产生新的试剂，进而可以进一步 探究免疫突触内的调节机制，并建立潜在的新药先导化合物 可以合理调节疾病的免疫反应。 在此应用中，我们将进一步开发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伙伴，并设计特定的界面。 还将探索协同结合计算和实验蛋白质工程技术。 将开发一种跨学科方法，其中通过计算设计、基于残留物的药效团 受体-配体界面的描述用于指导后续噬菌体展示中的文库设计 实验，允许有效探索工程结构，我们所有的计算结果将。 随后进行体外生化和细胞实验验证。 这些研究将直接扩展免疫中受体-配体对的当前知识库。 突触并产生突变分子，其对于治疗应用具有改变的亲和力和选择性。