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.

项目摘要 我们之前发现一个病人表现出痉挛性下肢轻瘫和其他神经症状 与ADGRB 2（也称为“BAI 2”）的羧基末端区域中的功能获得性突变相关 或“B2”），其是在中枢神经系统中最丰富表达的G蛋白偶联受体。 最近，临床医生联系了我们，他们发现了其他表现出痉挛的患者， 下肢轻瘫和窝藏突变的羧基末端区域的B2。我们建议重新研究这些- 鉴定突变，以确定它们是否以类似于突变的方式改变B2表达和信号传导活性。 与疾病相关的B2突变我们还建议研究基因敲入小鼠， 这些突变，以评估他们是否表现出任何病理，如运动功能的扰动， 可以模拟在人类患者中观察到的疾病。此外，我们建议研究一个潜在的B2配体， 我们最近发现的。这种潜在的配体是胎牛血清的一种成分， 以下观察表明表达B2的细胞的血清饥饿导致受体的显著增加， 表情考虑到该因子可以下调B2表达，并且激动剂的过度刺激可以抑制B2表达。 一个众所周知的G蛋白偶联受体下调的原因，我们将进行广泛的信号转导研究 来确定这个因子是否真的是B2激动剂这些研究将揭示生物学的基础， B2，还提供了对人类疾病治疗新途径的见解，包括患有 病理性ADGRB 2变异体以及表达野生型B2但患有 通过调节B2活性可以治疗的神经或精神疾病。