Determining the effect of INPP5D/SHIP1 deficiency in neuroinflammation and Alzheimer's disease pathologies

确定 INPP5D/SHIP1 缺陷对神经炎症和阿尔茨海默病病理学的影响

基本信息

批准号：
10728327
负责人：
Emilie Castranio
金额：
$ 7.88万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2022-09-30 至 2024-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10728327
关键词：
APP-PS1 Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Amyloidosis Anti-Inflammatory Agents Behavior Biochemistry Biological Assay Biological Response Modifiers Brain Brain Diseases Brain region Cause of Death Cell Surface Receptors Cells Cerebrum Clinic Cognition Cognitive deficits Dementia Deposition Disease Disease Outcome Elderly Equilibrium Evaluation Event FRAP1 gene Genes Genetic Recombination Genetic Transcription Genetic study Gliosis Goals Hematopoietic Heterogeneity Immunohistochemistry Microglia Modeling Mus Myeloid Cells Nature Neurodegenerative Disorders Osteoclasts Outcome PIK3CG gene PP5 protein-serine-threonine phosphatase Pathogenesis Pathogenicity Pathologic Pathology Pathway Analysis Pathway interactions Phagocytosis Phenotype Population Proliferating Receptor Activation Role Running Signal Pathway Signal Transduction TREM2 gene TYROBP gene Tamoxifen Tauopathies Testing Translating United States Up-Regulation Wild Type Mouse abeta accumulation abeta deposition amyloid pathology behavioral outcome drug testing extracellular gene network genetic variant genome sequencing genome wide association study hyperphosphorylated tau improved in vivo inducible Cre inositol-1,4,5-trisphosphate 5-phosphatase insight knock-down mouse model multiple omics neuroinflammation overexpression pharmacologic phosphoinositide-3,4,5-triphosphate phosphoinositide-3,4-bisphosphate prevent response risk variant single-cell RNA sequencing tau Proteins transcriptomics whole genome

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with aging and is the most common cause of dementia. In recent years, genetic studies have revealed a number of risk loci in or near genes expressed in microglia, suggesting a key role for microglia in AD pathogenesis. Inositol polyphosphate-5- phosphatase D (INPP5D) is one of the microglia-specific targets converged on by these genetic studies. INPP5D is primarily expressed by cells of the hematopoietic lineage, including microglia, and encodes a 5’ phosphatase protein known as SHIP1. INPP5D/SHIP1 is a negative regulator of immune cell surface receptors, including TREM2/TYROBP, by catalyzing the conversion of PI(3,4,5)P3 to PI(3,4)P2 to prevent receptor activation and downstream signaling, counteracting the PI3K/mTOR pathway. SHIP1 limits microglia functions associated with survival, proliferation and phagocytosis. INPP5D could be an important target for microglia-focused AD therapies, although it is still unknown how decreasing or increasing INPP5D expression affects pathology or behavioral outcomes in vivo. Inhibiting INPP5D expression promotes microglial proliferation, and phagocytosis, each of which is considered to be an important potential cellular phenotype for preventing or reducing AD pathology and improving disease outcomes. The aim of this proposal is to increase our understanding of the function of INPP5D/SHIP1 in the microglial response in diseased brain. We will use Inpp5dflox mice crossed with an inducible CX3CR1-CreER, in which tamoxifen-induced Cre expression results in persistent recombination in long-lived microglia, but not short-lived myeloid cells. For each aim, we will induce microglia-specific knockdown in models representing the pathological hallmarks of AD, Aβ deposition (APPKM670/671NL/PSEN1Δexon9) in Aim 1 and tauopathy (MAPTP301S) in Aim 2. We hypothesize that Inpp5d/SHIP1 deficiency outcomes are driven by TYROBP overexpression/upregulation, i.e. ameliorated pathogenic forms of amyloid pathology and cognitive deficits in amyloid mouse model but exacerbated tau pathology and cognitive deficits in tauopathy model. Importantly, pharmacological targeting both to activate and inhibit SHIP1 are being explored. It is necessary to understand the role of Inpp5d/SHIP1 in diseased brain before further drug testing. It is our hope that with the understanding gained in this proposal, we will be able to appropriately target Inpp5d/SHIP1 for disease and begin the next steps to test these compounds for their efficacy in brain with the intent to translate to the clinic.

项目摘要阿尔茨海默氏病（AD）是一种与衰老相关的进行性神经退行性疾病痴呆的常见原因。近年来，遗传研究揭示了基因或附近的许多风险基因座在小胶质细胞中表达，这表明小胶质细胞在AD发病机理中起关键作用。肌醇聚磷酸-5- 磷酸酶D（INPP5D）是这些遗传研究融合的小胶质细胞特异性靶标之一。 inpp5d 主要由包括小胶质细胞在内的造血谱系细胞表达，并编码5'磷酸酶蛋白质称为ship1。 Inpp5d/ship1是免疫球表面受体的负调节剂，包括 TREM2/Tyrobp，通过催化Pi（3,4,5）P3向Pi（3,4）P2的转化以防止受体激活和下游信号传导，抵消PI3K/mTOR途径。 Ship1限制了与生存，增殖和吞噬作用。 INPP5D可能是以小胶质细胞为中心的AD的重要目标疗法，尽管尚不清楚降低或增加INPP5D表达如何影响病理或体内行为结果。抑制INPP5D表达会促进小胶质细胞增殖和吞噬作用，每一个都被认为是预防或减少AD的重要潜在细胞表型病理学和改善疾病结局。该提案的目的是增加我们对小胶质中Inpp5d/ship1功能的理解解剖的大脑反应。我们将使用与诱导型CX3CR1-CRER交叉的Inpp5dflox小鼠，其中他莫昔芬诱导的CRE表达会导致长寿小胶质细胞的持续重组，但不是短暂的髓样细胞。对于每个目标，我们将诱导模型中的小胶质细胞特异性敲低代表病理 AIM 1中AD的标志，Aβ沉积（APPKM670/671NL/PSEN1ΔEXON9）和AIM 2中的Tauopathy（MAPTP301S）。假设INPP5D/Ship1缺乏效果是由Tyrobp的过表达/上调驱动的，即淀粉样小鼠模型中淀粉样病理学和认知缺陷的改善致病形式 Tauopathy模型中的TAU病理和认知缺陷加剧。重要的是，药物针对两者正在探索激活和抑制Ship1。有必要了解inpp5d/ship1在在进一步进行药物测试之前，患病的大脑。我们希望，随着该提议中获得的理解，我们将能够适当靶向疾病的INPP5D/Ship1，并开始测试这些化合物的下一步为了将大脑效率转化为诊所。