Synaptic function of BK channel-interacting proteins

BK 通道相互作用蛋白的突触功能

基本信息

批准号：
10712011
负责人：
ZHAO-WEN WANG
金额：
$ 39.17万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10712011
关键词：
Abeta synthesis Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Animal Model Award Brain Caenorhabditis elegans Calcium Clinical Trials Early Onset Familial Alzheimer&apos s Disease Endoplasmic Reticulum Enhancers Gene Expression Generations Genes Genetic Transcription Goals Hippocampus Human Knock-out Knowledge Link Mass Spectrum Analysis Messenger RNA Molecular Mus Mutation Nematoda Neurodegenerative Disorders Neuromuscular Junction Neurons Parents Pathogenesis Pattern Persons Phenotype Play Property Proteins Receptor Gene Research Role Ryanodine Receptor Calcium Release Channel Senile Plaques Synapses Synaptic Receptors Synaptic Transmission System Testing Translations Work abeta accumulation brain tissue candidate identification genetic regulatory protein inhibitor knock-down large-conductance calcium-activated potassium channels mutant neurotransmitter release postsynaptic presenilin presynaptic receptor expression receptor function synaptic function transcriptome sequencing

项目摘要

Alzheimer’s disease (AD) is a neurodegenerative disorder inflicting many people. Most cases of early-onset familial AD are linked to mutations of presenilins. Previous studies on presenilins have focused on their roles in the generation of amyloid β (Aβ) because accumulation of Aβ plaques in brain tissue is generally considered the primary cause of AD. However, the amyloid hypothesis is being questioned because all anti-amyloid clinical trials have failed. Therefore, it is necessary to explore other potential mechanisms of presenilin function in AD. Among the known effects of presenilin mutations are reduced neurotransmitter release and calcium dyshomeostasis, which are both putative underlying mechanisms of AD. It is known that mutations of presenilins cause reduced neurotransmitter release and calcium dyshomeostasis, which are associated with and potentially caused by decreased ryanodine receptor expression. However, it is unknown how presenilins regulate ryanodine receptors. This proposal is to test the hypothesis that presenilins regulate ryanodine receptor expression by acting through some other regulatory proteins. The nematode Caenorhabditis elegans is used as an animal model to identify the putative regulatory proteins because many cellular mechanisms in mammalian systems, including the roles of presenilins in synaptic and ryanodine receptor function, are conserved in worms. The specific aims of this proposal are: 1) identify candidates for the putative regulatory proteins of ryanodine receptor expression by mass spectrometry and RNA-seq, and 2) determine whether the identified proteins are required for presenilins’ roles in neurotransmitter release and ryanodine receptor expression. Our long-term goal is to illustrate whether and how reduced neurotransmitter release and ryanodine receptor function play a role in the pathogenesis of AD caused by presenilin mutations.

阿尔茨海默病 (AD) 是一种神经退行性疾病，大多数患者都是早发型。家族性 AD 与早老素突变有关。之前对早老素的研究主要集中在其在疾病中的作用。 β 淀粉样蛋白 (Aβ) 的产生，因为脑组织中 Aβ 斑块的积累通常被认为是然而，淀粉样蛋白假说受到质疑，因为所有抗淀粉样蛋白的临床试验。因此，有必要探索早老素在 AD 中发挥作用的其他潜在机制。早老素突变的已知影响是神经递质释放减少和钙稳态失调，这都是 AD 的假定潜在机制。众所周知，早老素的突变会导致 AD 的减少。神经递质释放和钙稳态失衡，与以下因素相关并可能由其引起：然而，早老素如何调节兰尼碱受体尚不清楚。该提案旨在检验早老素通过作用调节兰尼碱受体表达的假设线虫秀丽隐杆线虫被用作动物模型来鉴定。假定的调节蛋白，因为哺乳动物系统中的许多细胞机制，包括作用早老素在突触和兰尼碱受体功能中的作用在蠕虫中是保守的。建议是：1）通过质量鉴定兰尼碱受体表达的推定调节蛋白的候选者光谱测定和 RNA-seq，2) 确定所鉴定的蛋白质是否是早老素作用所必需的我们的长期目标是阐明是否以及神经递质释放和兰尼碱受体表达。神经递质释放和兰尼碱受体功能减少如何在 AD 发病机制中发挥作用由早老素突变引起。