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. ! !

项目概要 精神分裂症是一种毁灭性的精神疾病，影响约 1% 的美国人口。过去的事 几十年来，双胞胎研究和其他遗传分析已经证实，大约 80% 精神分裂症的风险是由于遗传性造成的，但目前只有少数基因得到明确的确定。 与这种明显的多基因疾病有关。因此，鉴定有助于 精神分裂症风险可以提供有关该疾病的新见解，并为治疗精神分裂症提供潜在的新途径。 治疗。最近，对大量多重精神分裂症家族的全外显子组分析揭示 脑血管生成抑制剂 1 (BAI1) 的一些突变与精神分裂症有关。 BAI1 是一个 已知调节树突棘和突触可塑性的突触受体，以及与 这些分析中的精神分裂症都是具有极高 CADD 评分的错义突变。我们将评估 这些与精神分裂症相关的突变对 BAI1 运输和信号活动的影响 以确定这些突变如何导致精神分裂症的发展。信令 研究将评估突变对 i) 受体的组成性信号活动和 ii) BAI1 与磷脂扰乱酶共表达所刺激的信号传导。在平行研究中，我们将 确定这种扰乱酶介导的 BAI1 信号传导增强是否是由于外化 磷脂酰丝氨酸，先前报道的 BAI1 胞外结构域的配体。因此，建议的 研究将为 BAI1 的基础生物学提供新的线索，同时评估 BAI1 的功能影响 精神分裂症相关的 BAI1 突变，目的是通过促进最终靶向该受体 小分子疗法可能对精神分裂症和其他精神科疾病有用的新疗法 失调。 ！ ！