IUSM Alzheimer's Disease Drug Discovery Center

IUSM 阿尔茨海默病药物研发中心

• 批准号: 10851513
• 负责人: Bruce T Lamb
• 金额: $ 35.12万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10851513
• 关键词: Aftercare; Algorithms; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Area; Base Sequence; Binding; Bioinformatics; Biological Assay; Brain; Cell surface; Cells; Clinic; Cognition; Complex; DNA; DNA Probes; Disease; Disease Progression; Disease associated microglia; Drug Targeting; Drug or chemical Tissue Distribution; Enzymes; Etiology; Family; Gene Expression Profile; Genes; Genetic; Health; Heterozygote; Human; Human Genetics; Immune; Immune response; Immunologic Receptors; Impaired cognition; Inflammatory; Investigation; Knock-out; Libraries; Luciferases; Messenger RNA; Methodology; Microglia; Mission; Modification; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Neurotoxins; Oligonucleotides; PLCG2 gene; Pathway interactions; Peripheral; Phase; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Plasmids; Play; Protein phosphatase; Reporter; Research; Risk; Role; Senile Plaques; Signal Transduction; Small Interfering RNA; Synapses; System; TREM2 gene; Technology; Testing; Translations; Tyrosine; United States National Institutes of Health; Validation; Variant; abeta oligomer; assay development; design; drug discovery; drug efficacy; immunoregulation; improved; in vivo; in vivo evaluation; inositol-1,4,5-trisphosphate 5-phosphatase; knock-down; member; mouse model; neurofibrillary tangle formation; neuroinflammation; neuropathology; neurotoxicity; nonhuman primate; novel therapeutics; receptor; risk variant; screening; tau Proteins; therapeutic siRNA; validation studies; β-amyloid burden; Aftercare; Algorithms; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Area; Base Sequence; Binding; Bioinformatics; Biological Assay; Brain; Cell surface; Cells; Clinic; Cognition; Complex; DNA; DNA Probes; Disease; Disease Progression; Disease associated microglia; Drug Targeting; Drug or chemical Tissue Distribution; Enzymes; Etiology; Family; Gene Expression Profile; Genes; Genetic; Health; Heterozygote; Human; Human Genetics; Immune; Immune response; Immunologic Receptors; Impaired cognition; Inflammatory; Investigation; Knock-out; Libraries; Luciferases; Messenger RNA; Methodology; Microglia; Mission; Modification; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Neurotoxins; Oligonucleotides; PLCG2 gene; Pathway interactions; Peripheral; Phase; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Plasmids; Play; Protein phosphatase; Reporter; Research; Risk; Role; Senile Plaques; Signal Transduction; Small Interfering RNA; Synapses; System; TREM2 gene; Technology; Testing; Translations; Tyrosine; United States National Institutes of Health; Validation; Variant; abeta oligomer; assay development; design; drug discovery; drug efficacy; immunoregulation; improved; in vivo; in vivo evaluation; inositol-1,4,5-trisphosphate 5-phosphatase; knock-down; member; mouse model; neurofibrillary tangle formation; neuroinflammation; neuropathology; neurotoxicity; nonhuman primate; novel therapeutics; receptor; risk variant; screening; tau Proteins; therapeutic siRNA; validation studies; β-amyloid burden

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a fatal neurodegenerative condition characterized by cognitive decline, β-amyloid (Aβ) plaques, and tau-containing neurofibrillary tangles (NFTs). Recent human genetic evidence supports an important role for microglia and neuroinflammation in the etiology of AD. Microglia are the resident immune cells in brain that maintain neuronal health and proper immunomodulation of neighboring glial cells. Microglia clear neurotoxins, Aβ oligomers, and Aβ plaques, and thereby mitigate an inflammatory microenvironment that is toxic to neurons. Genetic evidence suggests that lower expression of the cell surface microglial immune receptor known as Triggering receptor expressed on myeloid cells-2 (TREM2) and inactivating variants (e.g. R47H) of this receptor are correlated with an increased risk of developing of AD. Conversely, enhanced signaling downstream from TREM2 via the Phospholipase C gamma 2 (PLCγ2) P522R variant is protective. This genetic evidence suggests that dampened microglial activity increases risk of neurodegeneration while activated microglia are protective. Src homology 2 domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is a member of the inositol polyphosphate-5-phosphatase (INPP5D) family, which has also been identified as a risk gene for AD. INPP5D encodes SHIP1, which is a phosphatidylinositol phosphatase that plays a key role regulating pathways downstream from TREM2 by binding immunoreceptor tyrosine-based inhibition motifs (ITIMs), competing with kinases, and modulating phosphatidylinositol-dependent signaling. We hypothesize that knockdown of INPP5D/SHIP1 will increase signaling downstream from TREM2 thus increasing microglial protective functions, which will result in a reduced rate of disease progression and cognitive decline in AD patients. To test this hypothesis, we will design and synthesize oligonucleotides for the efficient siRNA knockdown of INPP5D (Aim 1). We will develop a screening assay for the selection of oligonucleotides with optimal knockdown efficiency (Aim 2). Importantly, these oligonucleotides will be modified for efficient tissue distribution and knockdown efficiency in brain, which will allow the investigation of INPP5D silencing on microglial activity and related immunological responses in the 5xFAD murine model of AD (Aim 3). Our robust methodologies aim to elucidate the mechanistic impacts of SHIP1 on neuroinflammation, synaptic integrity, and broader neuropathological sequela associated with AD. Collectively, these studies will support the translation of a therapeutic siRNA into the clinic that will reduce neuroinflammation, amyloid burden, and improve cognition, thus advancing the NIH/NIA mission to develop novel therapies for AD.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种致命的神经退行性疾病，其特征是认知能力下降，β-淀粉样蛋白 （Aβ）斑块和含tau的神经纤维缠结（NFTS）。最近的人类遗传证据支持 小胶质细胞和神经炎症的重要作用在AD的病因中。小胶质细胞是居民免疫细胞 在维持神经元健康和适当免疫调节的大脑中。小胶质细胞清晰 神经毒素，Aβ低聚物和Aβ斑块，从而减轻炎性微环境，这是有毒的 致神经元。遗传证据表明细胞表面小胶质细胞免疫接收器的表达较低 被称为在髓样细胞-2（Trem2）和灭活变体（例如R47H）上表达的受体 该接收器与AD发展的风险增加相关。相反，信号传导增强 通过磷脂酶C伽马2（PLCγ2）p522r变体从TREM2下游受到保护。这个通用 有证据表明，该死的小胶质细胞活性会增加神经退行性的风险。 小胶质细胞受到保护。 SRC同源性2结构域含有肌醇5-磷酸酶1（Ship1）为 肌醇聚磷酸5-磷酸酶（INPP5D）家族的成员，该家族也已被鉴定为 AD的风险基因。 INPP5D编码Ship1，这是一种磷脂酰肌醇磷酸酶，起着关键作用 通过结合免疫感受器酪氨酸抑制基序来调节TREM2下游的途径 （ITIMS），与激酶竞争，并调节磷脂酰肌醇依赖性信号传导。我们假设这一点 INPP5D/Ship1的敲低将增加TREM2下游的信号，从而增加小胶质细胞 保护功能，这将导致疾病进展率降低和AD认知能力下降 患者。为了检验这一假设，我们将设计和合成寡核苷酸的有效siRNA 击倒INPP5D（AIM 1）。我们将开发一个筛选测定法，以选择使用寡核苷酸 最佳敲低效率（AIM 2）。重要的是，这些寡核苷酸将被修改以进行有效的组织 大脑的分配和敲低效率，这将允许对小胶质细胞的INPP5D沉默进行投资 AD的5xFAD鼠模型中的活性和相关免疫反应（AIM 3）。我们的强大 旨在阐明Ship1对神经炎症，突触完整性和 与AD相关的更广泛的神经病理续集。总的来说，这些研究将支持翻译 进入诊所的治疗性siRNA，将减少神经炎症，淀粉样蛋白伯恩并改善认知， 因此，推进了NIH/NIA的使命，以开发AD的新型疗法。