Activation and Regulation of the Synaptic Receptor BAI1

项目摘要 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 几十年来，双胞胎研究和其他遗传分析已经确定，大约80%的 精神分裂症的风险是由于遗传性，但目前只有少数基因已明确 与这种明显的多基因疾病有关因此，鉴定其他基因，有助于 精神分裂症的风险可以提供有关疾病的新见解，也提出了潜在的新途径， 治疗最近，对一组广泛的多重精神分裂症家族的全外显子组分析显示， 脑血管生成抑制因子1（BAI 1）的几个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 在这些分析中，精神分裂症都是错义突变，具有极高的CADD评分。我们将评估 这些精神分裂症相关突变对BAI 1的运输和信号传导活性的影响， 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）受体的组成型信号传导活性和 ii）通过BAI 1与磷脂乱序酶的共表达刺激的信号传导。在平行研究中，我们将 确定这种扰乱酶介导的BAI1信号增强是否是由于 磷脂酰丝氨酸，先前报道的BAI1胞外结构域的配体。因此，拟议的 这些研究将为BAI 1的基础生物学提供新的线索，同时也评估了BAI 1的功能效应。 精神分裂症相关的BAI1突变，目的是促进这种受体的最终靶向， 可能是精神分裂症和其他精神疾病有用新疗法的小分子治疗剂 紊乱 ! !

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. ! !