Role of PLD3 in nucleic acid recognition and brain function

PLD3在核酸识别和脑功能中的作用

基本信息

批准号：
10525053
负责人：
DAVID NEMAZEE
金额：
$ 133.13万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525053
关键词：
APP-PS1 Address Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Biochemical Biological Biological Assay Brain Cell Culture Techniques Cells Crystallization DNA Defect Digestion Disease Double-Stranded RNA Enzymes Exonuclease Genes Genetic Polymorphism Goals Human Immune system Immunologics Inflammation Knock-in Late Onset Alzheimer Disease Ligands Link Measures Microglia Missense Mutation Modeling Mus Mutation Nerve Degeneration Neurons Nucleic Acids Pathology Phagocytes Phenotype Phospholipase Phospholipases A Proliferating Proteins RNA Resources Ribosomal RNA Risk Factors Role Single-Stranded DNA Spinocerebellar Ataxias Structure TLR3 gene TLR7 gene TLR8 gene Testing Thymus Gland Toll-like receptors Transgenes Type 1 Spinocerebellar Ataxia Variant Vesicle autoinflammation brain tissue genetic variant genome wide association study in vivo mouse model mutant nervous system disorder novel null mutation protein function receptor sensor stressor tau Proteins tool virtual

项目摘要

PROJECT SUMMARY/ABSTRACT This is a R01 proposal to study the function of Phospholipase D3 (PLD3) and its contribution to neurodegeneration in mouse models. PLD3 missense mutations and under expression have been implicated in Alzheimer's disease (AD) and in Spinocerebellar Ataxia, but the mechanisms by which these mutations alter function are unclear. PLD3 protein is associated with neuritic AD plaques and has been implicated in Ab and Tau processing. We have recently discovered that PLD3 and a related protein PLD4 are not phospholipases, as was thought, but are in fact single-stranded DNA and RNA exonucleases localized in endolysosomes. PLD3 and PLD4 can strongly influence nucleic acid recognition by Toll-like receptors (TLR) 7, 8 and 9. Mice lacking both PLD3 and PLD4 enzymes die of massive autoinflammation, whereas the phenotype of Pld3–/– mice is relatively subtle and has not been investigated in older mice. Here we propose to study the roles of PLD3 in more detail by evaluating functional alterations of disease associated PLD3 alleles and by generating tools to assess the effects of deficiency of PLD3 and PLD4 in microglia and other tissues of the brain. The ability of PLD3 deficiency to accelerate disease in the APP/PS1 model will also be investigated.

项目概要/摘要这是一项 R01 提案，旨在研究磷脂酶 D3 (PLD3) 的功能及其对小鼠模型中的神经变性与 PLD3 错义突变和表达不足有关。阿尔茨海默病 (AD) 和脊髓小脑性共济失调，但这些突变改变的机制 PLD3 蛋白与神经炎性 AD 斑块相关，并且与 Ab 和 AD 相关。我们最近发现 PLD3 和相关蛋白 PLD4 不是磷脂酶，因为被认为是单链 DNA 和 RNA 核酸外切酶，但实际上是位于内溶酶体中的单链 DNA 和 RNA 核酸外切酶。 PLD4 可强烈影响 Toll 样受体 (TLR) 7、8 和 9 的核酸识别。缺乏这两种受体的小鼠 PLD3和PLD4酶死于大量自身炎症，而Pld3–/–小鼠的表型相对较弱。微妙且尚未在老年小鼠中进行过研究，在此我们建议更详细地研究 PLD3 的作用。通过评估疾病相关 PLD3 等位基因的功能改变并生成工具来评估 PLD3 和 PLD4 缺乏对小胶质细胞和大脑其他组织的影响 PLD3 缺乏的能力。还将研究在 APP/PS1 模型中加速疾病的作用。