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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：
9925840
负责人：
Gek Ming Sia
金额：
$ 33.01万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925840
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.

项目总结/摘要突触的形成和消除是神经元组装所必需的基本过程。大脑中的神经回路这些过程中的缺陷导致突触密度异常，大脑，这被认为有助于许多神经发育障碍的发病机制。目标这项研究的目的是了解Sushi Repeat Protein X-linked 2（SRPX 2）如何调节突触。大脑中的密度。我们先前已经表明，寿司重复蛋白X连锁2（SRPX 2）基因编码一种神经元表达的分泌性突触发生蛋白，可增加皮质中兴奋性突触的密度，神经元Sushi重复序列主要存在于外周的已知补体调节子中。我们初步数据表明，SRPX 2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。为了验证这一假设，我们提出了以下目标。目标1：威慑- 如果SRPX 2信号通过经典补体途径调节突触密度和消除。目的2：确定SRPX 2是否通过与C1 q结合抑制经典补体级联反应。目标3：确定是否 SRPX 2在成人和老年大脑中是突触维持所必需的。我们预计，这些研究将为发育中的大脑中突触消除的分子机制提供了新的见解，可能会导致新的治疗方法，用于治疗发育和退行性脑疾病。