Disease-Associated Mutations and Ligand Activation of the Adhesion G Protein-Coupled Receptor ADGRB2

粘附 G 蛋白偶联受体 ADGRB2 的疾病相关突变和配体激活

• 批准号: 10811019
• 负责人: Randy A. Hall
• 金额: $ 43.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10811019
• 关键词: Adhesions; Agonist; Amaze; Amino Acids; Arrestins; Atrophic; BAI2 gene; Behavior; Biological Assay; Biology; Boston; Brain; C-terminal; Cell membrane; Cells; Central Nervous System; Clinical; Complex; Country; Cryoelectron Microscopy; Cytoplasm; Cytoplasmic Receptors; Data; Development; Disease; Disease model; Dose; Down-Regulation; Drug Targeting; Early identification; Endocytosis; England; Etiology; Exhibits; FDA approved; Family member; G-Protein-Coupled Receptors; Genes; Human; Hydrocortisone; In Vitro; Knock-in Mouse; Lead; Ligands; Link; Measures; Mental disorders; Monozygotic twins; Motor; Mus; Mutation; Neurodegenerative Disorders; Neurologic Symptoms; Neurologist; Pathologic; Pathology; Patients; Population Database; Progesterone; Progesterone Receptors; Receptor Down-Regulation; Serum; Signal Transduction; Spastic Paraparesis; Spinal Cord; Starvation; Steroids; Structure; Surface; System; Testing; Therapeutic; Time; Transfection; Variant; associated symptom; brief intervention; clinical phenotype; de novo mutation; fetal bovine serum; gain of function mutation; human disease; in vivo; insight; nervous system disorder; novel; novel therapeutics; patient population; pharmacologic; rare variant; receptor; receptor downregulation; receptor expression; receptor function; response; steroid hormone; tool

Project Summary We previously identified a patient exhibiting spastic paraparesis and other neurological symptoms associated with a gain-of-function mutation in the carboxyl-terminal region of ADGRB2 (also known as “BAI2” or “B2”), which is a G protein-coupled receptor most abundantly expressed in the central nervous system. Recently, we have been contacted by clinicians who have identified additional patients exhibiting spastic paraparesis and harboring mutations to the carboxyl-terminal region of B2. We propose to study these newly- identified mutations to determine if they alter B2 expression and signaling activity in a manner similar to the disease-associated B2 mutation that we identified earlier. We also propose to study knock-in mice harboring these mutations to assess whether they exhibit any pathology, such as perturbations of motor function, that might model the disease observed in the human patients. Moreover, we propose to study a potential B2 ligand that we have recently identified. This potential ligand is a component of fetal bovine serum and was isolated following observations that serum starvation of cells expressing B2 resulted in a dramatic increase in receptor expression. Given that this factor can down-regulate B2 expression, and that over-stimulation with agonists is a well-known cause of G protein-coupled receptor down-regulation, we will perform extensive signaling studies to determine if this factor is indeed a B2 agonist. These studies will shed light on the fundamental biology of B2 and also provide insights into new avenues of treatment for human disease, including patients harboring pathological ADGRB2 variants as well as the wider population of patients who express wild-type B2 but suffer from neurological or psychiatric disorders that might be treatable via modulation of B2 activity.

项目概要 我们之前发现一名患者表现出痉挛性截瘫和其他神经系统症状 与 ADGRB2（也称为“BAI2”）羧基末端区域的功能获得性突变相关 或“B2”），它是一种在中枢神经系统中表达最丰富的 G 蛋白偶联受体。 最近，圣人联系了我们，他们发现了更多表现出痉挛的患者 我们建议研究这些新的截瘫和 B2 羧基末端区域的突变。 鉴定突变以确定它们是否以类似于 我们之前发现了与疾病相关的 B2 突变，我们还建议研究携带该突变的基因敲入小鼠。 这些突变来评估它们是否表现出任何病理学，例如运动功能的扰动， 可能会模拟在人类患者中观察到的疾病。此外，我们建议研究潜在的 B2 配体。 我们最近鉴定出这种潜在的配体是胎牛血清的成分并被分离出来。 观察到表达 B2 的细胞的血清饥饿导致受体急剧增加 鉴于该因子可以下调 B2 表达，并且激动剂的过度刺激是 G 蛋白偶联受体下调的一个众所周知的原因，我们将进行广泛的信号研究 以确定该因子是否确实是 B2 激动剂，这些研究将揭示 B2 的基本生物学原理。 B2 还提供了对人类疾病治疗新途径的见解，包括携带病毒的患者 病理性 ADGRB2 变异以及更广泛的表达野生型 B2 但患有此病的患者群体 神经或精神疾病可通过调节 B2 活性来治疗。