权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Soluble TREM2 regulation of microglial function in Alzheimer disease

可溶性 TREM2 对阿尔茨海默病小胶质细胞功能的调节

基本信息

批准号：
10432584
负责人：
MARCO COLONNA
金额：
$ 43.06万
依托单位：
WASHINGTON UNIVERSITY
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：
2022-05-05 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432584
关键词：
Affect Age Alzheimer&apos s Disease American Amyloid beta-Protein Apoptotic Binding Binding Proteins Brain CRISPR/Cas technology Candidate Disease Gene Cause of Death Cells Chimeric Proteins Dementia Deposition Development Disease Engineering Functional disorder Genetic Human Immunologic Receptors Integral Membrane Protein Intrathecal Injections Knockout Mice Lipoproteins Membrane Microglia Modeling Mus Pathology Phagocytosis Phospholipids Prevention Proteins Regulation Risk Risk Factors Senile Plaques Signal Transduction Slice TREM2 gene TYROBP gene Time United States Variant beta amyloid pathology brain cell cognitive function cost estimate efficacy evaluation experimental study genetic variant genome wide association study improved mouse model novel strategies novel therapeutics protein aggregation receptor receptor binding therapy development tool whole genome

项目摘要

PROJECT SUMMARY Alzheimer's Disease (AD) is the 6th leading cause of death in the United States and more than 5.8 million Americans suffer from this disease. This year the estimated cost of AD and other dementias is $305 billion, and could rise to $1.1 trillion by 2050. The cause of AD remains elusive and is likely multifactorial. The greatest risk factors are known to be age, genetics, and inheritance. Genome-wide association studies have shown that variants of TREM2 are associated with two to four times the risk of developing AD. TREM2 is an innate immune receptor expressed in microglia that has been shown to interact with phospholipids, apoptotic cells, lipoproteins, and oligomeric forms of amyloid-β (Aβ). This protein has been shown to be required for microglial proliferation, survival, and phagocytosis of Aβ. TREM2 is a transmembrane protein with no intracellular signaling domains; signal transduction requires binding to DAP12. Upon microglial activation and clustering, TREM2 is cleaved from the membrane generating soluble TREM2 (sTREM2). Since both membrane-bound TREM2 and sTREM2 coexist during different stages of AD, it has been difficult to differentiate the extent of which each form independently contributes to disease pathology. It was recently shown that after intrathecal administration, sTREM2 binds to microglia, transmitting intracellular signals, promoting survival, improving cognitive function, and mitigating Aβ pathology; it has been postulated that sTREM2 acts through a putative yet unknown receptor. In this proposal we will utilize a CRISPR/Cas9 whole genome screen to identify the receptor that binds sTREM2 on microglia and promotes signal transduction. Identified candidate genes will be validated in human microglial cells and knockout mouse models will be generated to further explore the importance of each in the development of AD and its pathophysiology. These models will serve as tools that will permit us to identify how sTREM2 modulates microglia independently from membrane-bound TREM2. Such discovery will serve as the basis for novel therapeutics aimed at modulation of the sTREM2 receptor. sTREM2 has also been shown to bind Aβ plaques. We will exploit this observation and develop sTREM2-fraction crystallizable(sTREM2-Fc) fusion proteins that bind Aβ plaques and promote activation of microglia and phagocytosis. The sTREM2-Fc fusion proteins will be validated using slices of brains from 5XFAD mice that accumulate A plaques typical of AD. We will also perform intrathecal injections, which will allow us to evaluate the efficacy of sTREM2-Fc in eliminating plaques and activating microglia. Taken together, these are novel approaches that may help to develop therapies that enhance clearance and prevention of amyloid-β plaque formation for the treatment of AD.

项目总结