Activation and Regulation of the Synaptic Receptor BAI1

突触受体 BAI1 的激活和调节

• 批准号: 9900070
• 负责人: Randy A. Hall
• 金额: $ 23.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900070
• 关键词: ANXA5 gene; Affect; Amino Acid Substitution; Amino Acids; Angiogenesis Inhibitors; Apoptosis; Apoptotic; BAI1 gene; Binding; Biology; Brain; C2 Domain; Cell membrane; Cells; Chemosensitization; Coupling; Dendritic Spines; Development; Disease; Evolution; Excision; Exhibits; Extracellular Domain; Family; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic; Genetic study; Goals; Heritability; Hippocampus (Brain); Human; Institutes; Knock-out; Knockout Mice; Ligands; Light; Link; Mediating; Mental disorders; Missense Mutation; Mus; Mutate; Mutation; Neuraxis; Neurons; Other Genetics; Pathology; Pathway interactions; Phosphatidylserines; Physiological; Population; Proteins; Receptor Signaling; Regulation; Reporting; Risk; Rodent; Role; Schizophrenia; Signal Pathway; Signal Transduction; Stimulus; Structure; Surface; Synapses; Synaptic Receptors; Synaptic plasticity; Testing; Transfection; Twin Studies; Universities; Work; density; exome; extracellular; genetic analysis; insight; member; mutant; novel; phospholipid scramblase; rare variant; receptor; small molecule therapeutics; trafficking

Project Summary Schizophrenia is a devastating psychiatric disorder that affects ~1% of the USA population. Over the past few decades, twin studies and other genetic analyses have established that approximately 80% of schizophrenia risk is due to heritability, but at present only a small number of genes have been definitively linked to this clearly polygenic disorder. Thus, the identification of additional genes that contribute to schizophrenia risk can provide new insights about the disease and also suggest potential new avenues for treatment. Recently, whole-exome analyses of an extensive set of multiplex schizophrenia families revealed several mutations in the brain angiogenesis inhibitor 1 (BAI1) to be associated with schizophrenia. BAI1 is a synaptic receptor known to regulate dendritic spines and synaptic plasticity, and the BAI1 mutations linked to schizophrenia in these analyses are all missense mutations with extremely high CADD scores. We will assess the effects of these schizophrenia-associated mutations on the trafficking and signaling activity of BAI1 in order to determine how these mutations may be contributing to the development of schizophrenia. The signaling studies will assess the effects of the mutations on both i) constitutive signaling activity by the receptor and ii) signaling stimulated by co-expression of BAI1 with phospholipid scramblases. In parallel studies, we will determine whether this scramblase-mediated potentiation of BAI1 signaling is due to externalization of phosphatidylserine, a previously reported ligand for the extracellular domains of BAI1. Thus, the proposed studies will shed new light on the fundamental biology of BAI1 while also assessing the functional effects of the schizophrenia-associated BAI1 mutations, with the goal of facilitating the eventual targeting of this receptor by small molecule therapeutics that may be useful new treatments for schizophrenia and other psychiatric disorders. ! !

项目摘要 精神分裂症是一种毁灭性的精神疾病，影响了约1％的美国人群。过去 几十年来，双胞胎研究和其他遗传分析已经确定了约80％ 精神分裂症的风险是由于遗传力，但目前只有少数基因是确定的 与这种明显的多基因疾病有关。因此，鉴定有助于 精神分裂症的风险可以提供有关该疾病的新见解，也暗示了潜在的新途径 治疗。最近，对一组多重精神分裂症系列的全面分析显示 与精神分裂症有关的脑血管生成抑制剂1（BAI1）中的几个突变。 bai1是一个 已知的突触受体调节树突状刺和突触可塑性，而BAI1突变与 这些分析中的精神分裂症都是cadd得分极高的错义突变。我们将评估 这些精神分裂症相关的突变对BAI1的运输和信号活性的影响 确定这些突变如何有助于精神分裂症的发展。信号传导 研究将评估突变对两者的影响i）受体的本构信号传导活性和 ii）通过与磷脂串联酶共表达BAI1刺激的信号传导。在平行研究中，我们将 确定Bai1信号的这种拼盘酶介导的增强是否是由于外部化 磷脂酰丝氨酸，这是BAI1细胞外域的先前报道的配体。因此，提议 研究将对BAI1的基本生物学发明新的启示，同时还评估了功能效应 精神分裂症相关的BAI1突变，目的是促进该受体最终靶向该受体 小分子疗法可能是精神分裂症和其他精神病学的有用的新疗法 疾病。 呢 呢