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，影响着美国约1%的人口。在过去的时间里 几十年来，双胞胎研究和其他遗传分析已经证实，大约80%的 精神分裂症的风险是由遗传性引起的，但目前只有少量基因被确定 与这种明显的多基因疾病有关。因此，识别其他有助于 精神分裂症的风险可以提供关于这种疾病的新见解，也可以为 治疗。最近，对一组广泛的多元化精神分裂症家庭的全基因组分析揭示了 脑血管生成抑制因子1(BAI1)的几个突变与精神分裂症有关。BAI1是一个 已知的突触受体调节树突棘和突触可塑性，BAI1突变与 这些分析中的精神分裂症都是错义突变，CADD得分极高。我们将评估 这些精神分裂症相关突变对BAI1转运和信号活性的影响 以确定这些突变可能如何导致精神分裂症的发展。信令 研究将评估突变对两个方面的影响：1)受体和 Ii)BAI1和磷脂扰乱酶共表达刺激的信号转导。在平行研究中，我们将 确定这种扰乱酶介导的BAI1信号增强是否是由于 磷脂酰丝氨酸，先前报道的BAI1胞外区的配体。因此，拟议的 研究将为BAI1的基础生物学提供新的线索，同时也将评估BAI1的功能影响 与精神分裂症相关的BAI1突变，目的是促进该受体的最终靶向 小分子疗法可能是治疗精神分裂症和其他精神疾病的有用的新疗法 精神错乱。 好了！ 好了！