Structural and Functional Studies of Cell-Adhesion Receptors

细胞粘附受体的结构和功能研究

• 批准号: 10557708
• 负责人: Demet Arac-Ozkan
• 金额: $ 28.25万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557708
• 关键词: Adhesions; Biochemical; Biological Assay; Biophysics; Cell Adhesion; Cell Surface Receptors; Cell physiology; Communication; Communities; Complement; Complex; Development; Disease; Eukaryota; Evolution; FDA approved; Family; Future; G-Protein-Coupled Receptors; Genetic study; Goals; Heart; Knowledge; Ligands; Link; Malignant Neoplasms; Mediating; Molecular; Mutagenesis; Mutate; Nature; Organism; Pharmaceutical Preparations; Physiological; Protein Engineering; Research; Role; Signal Transduction; Skeletal system; Structure; Testing; Therapeutic; Work; adhesion receptor; brain malformation; developmental disease; extracellular; human disease; insight; intercellular communication; interdisciplinary approach; malignant neurologic neoplasms; nervous system development; nervous system disorder; novel strategies; programs; receptor; receptor function; success; three dimensional structure; tool

Project Abstract Cellular communication is essential for the development of all multicellular organisms, and is a key phenomenon that is disrupted in many human diseases. Cell-surface receptors mediate cellular communication and are the targets for 50% of FDA-approved drugs, highlighting their disease relevance and druggability. However, many cell-surface receptors remain understudied and undrugged. The research proposed in this application is focused on two families of such receptors, adhesion G Protein-Coupled Receptors (aGPCRs), and teneurins. The structures, mechanisms of action and disease relevance of these two receptor families remain largely unknown; as their large size and complex biochemical nature has made them difficult to study. Recent genetic studies revealed that aGPCRs and teneurins have essential roles in development of the nervous system, skeletal system, and heart. These receptors are linked to diseases including cancer, developmental disorders, and brain malformations, raising an urgent need for mechanistic studies on aGPCRs and teneurins. My research program aims to elucidate the molecular mechanisms by which these receptors are activated, and to develop new tools to modulate their activity against relevant diseases. The research proposed in this application involves an interdisciplinary approach, integrating structural studies of these receptors and their ligands, biochemical and biophysical assays, protein engineering approaches, and functional assays. This research will build on our previous successes using this approach, which has yielded many three-dimensional structures of aGPCRs and teneurins, has revealed crucial mechanistic concepts in the field, and has allowed a better understanding of the mechanisms of action of these receptors. A major revelation from our work is that the large extracellular regions of aGPCRs and teneurins are directly involved in regulating receptor function. Despite these advances, fundamental questions remain unanswered. The ultimate goals of this proposal are to reveal how signal transduction is mediated within the domains of these large receptors, what exactly activates them under physiological conditions, how their evolution from early organisms to higher eukaryotes have changed and diversified their critical functions, and finally how, at the molecular level, we can inhibit or activate these receptors using synthetic ligands. Our structural studies will be complemented with mutagenesis, signaling assays, the use of synthetic binders to understand how the different components of these receptors control receptor function, and physiological analyses performed by collaborators that will test the relevance of the structural and functional studies. We expect that this research will provide critical insights into the mechanistic details of aGPCR and teneurin function that will be highly informative for the development of future therapeutics; we will also produce potent and selective synthetic ligands which can serve as tools for the scientific community to study aGPCRs and teneurins.

项目摘要 细胞通信对于所有多细胞生物的发展至关重要，并且是关键现象 这在许多人类疾病中受到了破坏。细胞表面受体介导细胞通信，是 50％的FDA批准药物的靶标突出了它们的疾病相关性和可药用。但是，很多 细胞表面受体仍在研究和未策划。本应用程序中提出的研究集中 在两个此类受体的家族中，粘附G蛋白偶联受体（AGPCR）和teneurins。这 这两个受体家族的结构，作用机理和疾病相关性仍然很大未知； 由于它们的大小和复杂的生化性质使它们难以研究。最近的遗传研究 揭示了AGPCR和替核蛋白在神经系统的发展中具有重要作用 系统和心。这些受体与包括癌症，发育障碍和大脑在内的疾病有关 畸形，迫切需要对AGPCR和替代蛋白的机械研究。我的研究计划 旨在阐明这些受体被激活的分子机制，并开发新工具 调节其针对相关疾病的活动。该应用中提出的研究涉及 跨学科方法，整合这些受体及其配体的结构研究，生化和 生物物理测定，蛋白质工程方法和功能测定。这项研究将基于我们 使用这种方法取得了以前的成功，该方法产生了许多三维结构的AGPCR和 teneurins在该领域揭示了关键的机械概念，并可以更好地理解 这些受体的作用机理。我们工作的一个重大启示是大细胞外区域 AGPCR和Teneurins的含量直接参与调节受体功能。尽管有这些进步， 基本问题仍未得到答复。该提议的最终目标是揭示信号如何 转导在这些大受体的域内介导，是什么使它们在下面激活 生理条件，它们从早期生物到更高真核生物的发展如何发生变化，并且 多样化它们的关键功能，最后如何在分子水平上抑制或激活这些受体 使用合成配体。我们的结构研究将与诱变，信号测定和使用相辅相成 合成粘合剂的了解，以了解这些受体的不同成分如何控制受体功能， 以及合作者进行的生理分析，这些分析将测试结构和功能的相关性 研究。我们希望这项研究将为AGPCR和 对未来疗法的发展将有很大信息的纽布蛋白功能；我们还将生产 有效和选择性的合成配体可以作为科学界研究AGPCR的工具 和teneurins。