The Neuroprotective Role of PPAR-delta in Microglia

PPAR-δ 在小胶质细胞中的神经保护作用

基本信息

批准号：
10751623
负责人：
Jacob Sahag Deyell
金额：
$ 5.27万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751623
关键词：
Adipocytes Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid beta-Protein Anti-Inflammatory Agents Attenuated Brain Cell model Cells Central Nervous System Clinical Treatment Clinical Trials Data Dependence Disease Down-Regulation Exhibits Experimental Autoimmune Encephalomyelitis Exposure to Family Gene Activation Gene Expression Regulation Genes Genetic Transcription Goals Homeostasis Human Huntington Disease Immune Impaired cognition Inflammation Inflammatory Ligands Light Link Mediator Membrane Memory Loss Microglia Modeling Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders PPAR delta PTEN gene Parkinson Disease Pathogenesis Peroxisome Proliferator-Activated Receptors Phagocytes Phase Phenotype Play Pluripotent Stem Cells Prevalence Process Production Quality of life Research Role SIRT1 gene TYROBP gene Tauopathies Testing Therapeutic Transactivation Transcription Coactivator Transcriptional Regulation Translating Wild Type Mouse Work apolipoprotein E-4 brain cell cytokine disease phenotype genetic risk factor improved in vitro Model in vivo induced pluripotent stem cell inflammatory marker insight member mouse model neuroinflammation neuroprotection novel therapeutic intervention risk variant tau Proteins therapeutic target transcription factor transcriptome sequencing uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive impairment. AD leads to a significant reduction in quality of life, and with a rapidly growing prevalence, there is a dire need for improved therapies. Peroxisome Proliferator-Activated Receptor delta (PPARd) is a ligand activated transcription factor that has emerged as a potential target for neuroprotection. PPARd agonism has been shown to improve disease phenotypes in neurodegenerative disease model mice, and disruption of PPARd function in the central nervous system (CNS) of normal mice has been shown to elicit neurodegeneration. PPARd agonism is also currently in a Phase 2a clinical trial for treatment of mild-to-moderate AD. Of all the brain cells, microglia express PPARd most highly; however, the mechanistic basis of PPARd activity in microglia remains undefined. Microglia are the resident immune cells of the CNS and have been repeatedly implicated in the pathogenesis of AD, so understanding the role of PPARd in microglia will provide insight into its therapeutic value. Preliminary data reveals that PPARd can suppress inflammation in the brains of Huntington’s disease, Parkinson’s disease and tauopathy model mice. Additionally, preliminary RNA-sequencing data on isolated microglia from wild-type mice treated with the PPARd agonist KD3010 shows that PPARd agonism leads to downregulation of inflammatory genes (e.g. Il-1b and SPP1) as well as the downregulation of several AD relevant genes in microglia (e.g. C1QA/C1QB, IL12b and TYROBP). Microglia have been shown to take on aberrant phenotypes in disease settings. These altered phenotypes have been shown to be cell-autonomous in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs) that harbor mutations relevant to AD. For example, APOE4 microglia have been shown to exhibit reduced uptake of beta-amyloid, have shortened processes, and have increased pro-inflammatory cytokine secretion. iMGLs are powerful models for human microglia, as they are transcriptionally and phenotypically similar. This proposal will uncover the mechanistic basis of PPARd function in microglia and interrogate whether PPARd agonism can attenuate the aberrant phenotypes seen in microglia in the context of AD. I will first assess whether PPARd transactivation of neuroprotective targets is dependent upon phase separation with the transcriptional coactivator Mediator 1 and whether PU.1, which is a genetic risk factor for AD, interferes with PPARd neuroprotection. I will then derive iMGLs from iPSCs that harbor an AD risk allele (APOE4) to assess whether PPARd can attenuate the abnormal phenotypes, focusing on cytokine secretion and phagocytic capacity. Understanding the role that PPARd plays in microglia and how its activation affects microglia in an AD- relevant setting has the potential to provide further support as to why PPARd agonism should continue to be pursued as a therapeutic for AD.

项目概要/摘要阿尔茨海默病（AD）是一种神经退行性疾病，其特征是进行性记忆丧失和认知障碍导致生活质量显着下降，并迅速增长。流行，迫切需要改进的治疗方法。 (PPARd) 是一种配体激活的转录因子，已成为神经保护的潜在靶点。 PPARd 激动剂已被证明可以改善神经退行性疾病模型小鼠的疾病表型，正常小鼠中枢神经系统 (CNS) 中 PPARd 功能的破坏已被证明会引起 PPARd 激动剂目前也处于治疗轻度至中度神经退行性疾病的 2a 期临床试验中。 AD. 在所有脑细胞中，小胶质细胞表达 PPARd 的程度最高；然而，这是 PPARd 的机制基础。小胶质细胞的活性仍不清楚。小胶质细胞是中枢神经系统的常驻免疫细胞，目前尚未明确。反复涉及 AD 的发病机制，因此了解 PPARd 在小胶质细胞中的作用将提供深入了解其治疗价值。初步数据显示 PPARd 可以抑制亨廷顿舞蹈病患者大脑中的炎症，此外，帕金森病和 tau 蛋白病模型小鼠的初步 RNA 测序数据。用 PPARd 激动剂 KD3010 处理的野生型小鼠的小胶质细胞显示，PPARd 激动剂会导致炎症基因（例如 Il-1b 和 SPP1）的下调以及一些 AD 相关基因的下调小胶质细胞中的基因（例如 C1QA/C1QB、IL12b 和 TYROBP）已被证明呈现异常。疾病环境中的表型已被证明在人类中是细胞自主的。诱导多能干细胞 (iPSC) 衍生的小胶质细胞样细胞 (iMGL) 含有与 AD 相关的突变。例如，APOE4 小胶质细胞已被证明表现出对 β-淀粉样蛋白的摄取减少，缩短了过程，并增加促炎细胞因子分泌，是人类的强大模型。小胶质细胞，因为它们在转录和表型上相似。该提案将揭示小胶质细胞中 PPARd 功能的机制基础，并探讨是否 PPARd 激动剂可以减弱 AD 背景下小胶质细胞中出现的异常表型。 PPARd 神经保护靶标的反式激活是否依赖于与 PPARd 的相分离转录共激活因子 Mediator 1 以及 AD 遗传危险因素 PU.1 是否会干扰然后，我将从含有 AD 风险等位基因 (APOE4) 的 iPSC 中提取 iMGL 来进行评估。 PPARd是否可以减弱异常表型，重点关注细胞因子分泌和吞噬了解 PPARd 在小胶质细胞中的作用以及其激活如何影响 AD 中的小胶质细胞。相关环境有可能为为什么 PPARd 激动剂应继续发挥作用提供进一步的支持。被视为 AD 的治疗方法。