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 细胞通讯对所有多细胞生物的发育都是必不可少的，也是一种关键现象 这在许多人类疾病中都被破坏了。细胞表面受体介导细胞通讯，是 FDA批准的50%药物的目标，强调它们与疾病的相关性和可药性。然而，许多人 细胞表面受体仍未得到充分研究，也未被下药。在本申请中提出的研究重点是 在两个这类受体家族上，黏附G蛋白偶联受体(AGPCRs)和Teneurins。这个 这两个受体家族的结构、作用机制和疾病相关性在很大程度上仍不清楚； 由于其庞大的体型和复杂的生化性质，使它们的研究变得困难。最近的遗传学研究 揭示了aGPCRs和Teneurin在神经系统、骨骼发育中的重要作用 系统和心脏。这些受体与癌症、发育障碍和大脑等疾病有关 因此，迫切需要对aGPCRs和Teneurin进行机制研究。我的研究计划 旨在阐明这些受体被激活的分子机制，并开发新的工具 来调节他们对抗相关疾病的活动。本申请中提出的研究涉及一种 跨学科的方法，整合这些受体及其配体的结构研究，生化和 生物物理分析、蛋白质工程方法和功能分析。这项研究将建立在我们的 以前使用这种方法的成功，它已经产生了许多aGPCRs的三维结构和 Teneurins，揭示了该领域的关键机械概念，并使人们能够更好地理解 这些受体的作用机制。从我们的工作中得到的一个主要启示是，大的细胞外区域 AGPCRs和Teneurin直接参与调节受体功能。尽管有这些进步， 根本问题仍未得到解答。这项提议的最终目标是揭示如何发出信号 转导是在这些大受体的区域内进行的，到底是什么激活了它们 生理条件，它们从早期生物到高等真核生物的进化是如何变化的 使它们的关键功能多样化，最后，在分子水平上，我们如何抑制或激活这些受体 使用合成配体。我们的结构研究将与突变、信号分析、使用 以了解这些受体的不同成分如何控制受体的功能， 以及由合作者进行的生理分析，将测试结构和功能的相关性 学习。我们期望这项研究将对aGPCRa的机制细节和 Teneurin功能，将为未来治疗学的发展提供高度信息；我们还将生产 可作为科学界研究aGPCRs的工具的有效和选择性的合成配体 和Teneurins