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

The role of platinum-regulated lipid metabolism in tau-related dementia

铂调节的脂质代谢在 tau 相关痴呆中的作用

基本信息

批准号：
10713249
负责人：
Lingtao Jin
金额：
$ 41.22万
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：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713249
关键词：
Affect Alzheimer&apos s Disease Astrocytes Astrocytosis Brain Cancer Patient Carboplatin Cells Chemotherapy-Oncologic Procedure Cisplatin Cognitive Communication Complex Data Dementia Dendritic Cells Development Disease Progression Exhibits Fatty Acids Functional disorder Genes Glutamine Homeostasis Immune In Vitro Infiltration Inflammatory Knowledge Link Lipids Malignant Neoplasms Mediating Metabolism Microglia Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Pathogenesis Pathologic Pathology Phenotype Platinum Platinum Compounds Play Production Proteins Regulation Role Severities Severity of illness Signal Transduction Structural defect TREM2 gene Tauopathies Testing Toxic effect Tumor-Derived anti-cancer cancer cell chemotherapy exosome genetic variant genome wide association study in vivo in vivo Model lipid metabolism long chain fatty acid neuroinflammation neurotoxicity non-genetic prevent programs response risk variant tau Proteins tau aggregation tau mutation therapeutically effective tumor tumor microenvironment uptake

项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is characterized by widely distributed neurofibrillary tangles (NFTs), which plays an important role in AD pathogenesis. NFTs are composed of abnormal tau aggregates filling the neurons. Pathologic tau can activate the proinflammatory signaling in microglia and induce neuroinflammation, which forms a “vicious cycle” and significantly contributes to the disease progression and severity of AD. Moreover, activated microglia can subsequently cause a pronounced transformation of astrocytes called "reactive astrocytosis", leading to substantial neurotoxicity in AD. Increasing evidence demonstrate a critical role of aberrant microglial lipid metabolism in AD. Microglia exhibit a “lacy” phenotype featuring highly enriched lipid droplets, and lipid-laden microglia represent a dysfunctional and proinflammatory state. These observations all point to an important functional link between aberrant lipid metabolism, microglial dysfunction, and neuroinflammation. However, there are still significant knowledge gaps in understanding the complex network including both genetic variants and non-genetic insults that induces lipid-mediated microglial dysfunction. We previously uncovered that tumor-derived long-chain fatty acids critically contribute to lipid accumulation and consequently dysfunction of tumor-infiltrating dendritic cells. Our preliminary data also discovered that platinum agent (e.g. cisplatin and carboplatin), one of the most widely used chemotherapy agents for a variety of cancers, further exacerbates lipid accumulation and dysfunction of dendritic cells through reprograming of lipid metabolism in cancer cells. While studying how platinum treatment affects lipid metabolism in cancer cells as well as surrounding immune cells, we unexpectedly discovered that platinum also induces aberrant lipid accumulation in the brain, particularly in microglia. Importantly, this platinum-induced reprograming of lipid metabolism is associated with tau pathology in vivo. Therefore, the recently discovered neuron-microglia “lipid communication” may be impacted by platinum treatment, which may contribute to neuroinflammation, pathologic tau spreading and AD disease progression. We hypothesize that, platinum treatment, through reprograming lipid metabolism in neurons, promotes production of neuron-derived, fatty acids-enriched exosomes, which leads to lipid accumulation in surrounding microglia. This platinum-induced lipid accumulation consequently induces proinflammatory state of microglia and drives neuroinflammation, which further promotes pathological tau spreading and severity of AD. We will test our hypothesis through the following aims: Aim 1: To investigate the mechanism by which platinum drives microglial lipid accumulation. Aim 2: To elucidate how platinum-induced neuron/microglial lipid reprogramming promotes neuroinflammation and AD progression.

项目总结