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：
10388543
负责人：
DAVID NEMAZEE
金额：
$ 44.38万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388543
关键词：
Active Sites Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Biological Biological Assay Brain CRISPR/Cas technology Cell Culture Techniques Cells DNA Data Defect Dendritic Cells Digestion Disease Double-Stranded RNA Enzymes Exonuclease Genes Genetic Polymorphism Goals Human Immune system Immunologics Inflammation Lead Ligands Measures Microbe Microglia Missense Mutation Modeling Mus Mutation Nerve Degeneration Neurons Nucleic Acids Pathology Phagocytes Phenotype Phospholipase Phospholipases A Proliferating Proteins RNA Resources Risk Factors Role Single-Stranded DNA Spinocerebellar Ataxias TLR3 gene TLR7 gene TLR8 gene TREM2 gene Tamoxifen Testing Thymus Gland Tissues Toll-like receptors Transgenes Transgenic Mice Variant Vesicle autoinflammation brain tissue cytokine disease-causing mutation disorder risk genetic variant genome wide association study in vivo interest macrophage mouse model nervous system disorder null mutation presenilin-1 protein function receptor response sensor tau Proteins tool

项目摘要

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.

这是研究磷脂酶D3（PLD3）功能及其对小鼠模型中的神经变性。 PLD3错义突变和表达不足在阿尔茨海默氏病（AD）和脊椎动物共济失调中实施，但是这些突变改变功能尚不清楚。 PLD3蛋白与神经AD有关斑块已在AB和TAU加工中暗示。我们最近发现如前所述，PLD3和相关蛋白PLD4不是磷脂酶酶滞留的DNA和RNA外核酸酶局部局部在内溶液中。 PLD3和PLD4可以强烈影响Toll样受体（TLR）7,8和9。缺乏PLD3的小鼠的核酸识别和PLD4酶死于大规模自身炎症，而PLD3 - / - 小鼠的表型为相关的微妙，尚未在老鼠中进行研究。在这里，我们建议研究角色通过评估疾病相关PLD3等位基因的功能改变，可以详细详细介绍PLD3 并生成工具来评估PLD3和PLD4在小胶质细胞和大脑的其他组织。