Sushi domain proteins as synapse protective factors in brain development and aging

寿司结构域蛋白作为大脑发育和衰老中的突触保护因子

基本信息

批准号：
10591981
负责人：
Gek Ming Sia
金额：
$ 11.28万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2023-01-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10591981
关键词：
Address Adult Age Aging Alleles Alzheimer&apos s Disease Binding Biological Assay Brain Brain Diseases Classical Complement Pathway Code Complement Complement 1q Complement Activation Data Defect Deposition Development Dose Endogenous Factors Excitatory Synapse Genes Goals Hippocampus (Brain)Immunoassay In Vitro Knockout Mice Lead Link Maintenance Mediating Mediator of activation protein Memory Microglia Molecular Mus Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Pathogenesis Phenotype Process Proteins Proteomics Regulation Research Role Signal Transduction Slice Somatosensory Cortex Stains Structure Sushi Domain Synapses Tertiary Protein Structure Testing Thalamic structure Visual Work aged aging brain base comparative complement system density experimental study in vitro activity in vivo insight nervous system disorder neural circuit novel novel therapeutic intervention postsynaptic protective factors retinogeniculate social synaptogenesis

项目摘要

Project Summary/Abstract Synapse formation and elimination are fundamental processes that is essential for the assembly of neural circuits in the brain during development. Defects in these processes result in abnormal synaptic densities in the brain, which is believed to contribute towards the pathogenesis of many neurodevelopmental disorders. The goal of the proposed research is to understand how Sushi Repeat Protein X-linked 2 (SRPX2) regulates synapse density in the brain. We have previously shown that the sushi repeat protein X-linked 2 (SRPX2) gene codes for a neuronally-expressed secreted synaptogenic protein that increases the density of excitatory synapses in cor- tical neurons. Sushi repeats are predominantly found in known complement regulators in the periphery. Our preliminary data suggests that SRPX2 inhibits complement activation in the brain, thereby decreasing synapse pruning and increasing synapse density. To test this hypothesis, we proposed the following aims. Aim 1: Deter- mine if SRPX2 signals through the classical complement pathway to regulate synapse density and elimination. Aim 2: Determine if SRPX2 inhibits the classical complement cascade by binding to C1q. Aim 3: Determine if SRPX2 is required in the adult and aged brain for synapse maintenance. We anticipate that these studies will provide new insights into the molecular mechanisms underlying synapse elimination in the developing brain, and may lead to novel therapeutic approaches for treating developmental and degenerative brain disorders.

项目概要/摘要突触的形成和消除是神经元组装所必需的基本过程发育过程中大脑中的回路。这些过程的缺陷会导致突触密度异常大脑，据信它与许多神经发育障碍的发病机制有关。目标拟议研究的目的是了解 Sushi Repeat Protein X-linked 2 (SRPX2) 如何调节突触大脑中的密度。我们之前已经证明寿司重复蛋白 X 连锁 2 (SRPX2) 基因编码一种神经元表达的分泌性突触蛋白，可增加神经元兴奋性突触的密度神经元。 Sushi 重复序列主要存在于外周已知的补体调节因子中。我们的初步数据表明 SRPX2 抑制大脑中的补体激活，从而减少突触修剪和增加突触密度。为了检验这一假设，我们提出了以下目标。目标 1：阻止我认为 SRPX2 是否通过经典补体途径发出信号来调节突触密度和消除。目标 2：确定 SRPX2 是否通过与 C1q 结合来抑制经典补体级联。目标 3：确定是否成人和老年大脑需要 SRPX2 来维持突触。我们预计这些研究将为发育中大脑中突触消除的分子机制提供新的见解，并且可能会带来治疗发育性和退行性脑部疾病的新治疗方法。