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

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.

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以认知功能减退、β-淀粉样蛋白（β-amyloid，β-amyloid）、阿尔茨海默病（Alzheimer's disease，AD）和阿尔茨海默病（Alzheimer's disease，AD）为特征的神经退行性疾病。 （Aβ）斑块和含tau蛋白的神经元缠结（NFT）。最近的人类基因证据支持 小胶质细胞和神经炎症在AD病因中的重要作用。小胶质细胞是常驻免疫细胞 在维持神经元健康和邻近神经胶质细胞适当免疫调节脑中。小胶质细胞清除 神经毒素、Aβ寡聚体和Aβ斑块，从而减轻毒性的炎症微环境 到神经元遗传学证据表明，细胞表面小胶质细胞免疫受体的低表达 称为髓样细胞上表达的触发受体-2（TREM 2）和TREM 2的失活变体（例如R47 H）。 这种受体与AD发病风险增加相关。相反，增强的信号 通过磷脂酶C γ 2（PLCγ2）P522 R变体在TREM 2下游的作用是保护性的。这种遗传 有证据表明，当小胶质细胞激活时， 小胶质细胞具有保护作用。含Src同源2结构域的肌醇多磷酸5-磷酸酶1（SHIP 1）是 肌醇多磷酸-5-磷酸酶（INPP 5D）家族的成员，其也已被鉴定为 AD的危险基因INPP 5D编码SHIP 1，SHIP 1是一种磷脂酰肌醇磷酸酶，在细胞内起关键作用， 通过结合基于免疫受体酪氨酸的抑制基序调节TREM 2下游的途径 在一些实施方案中，ITIM与激酶竞争，并调节磷脂酰肌醇依赖性信号传导。我们假设 INPP 5D/SHIP 1的敲低将增加TREM 2下游的信号传导，从而增加小胶质细胞的增殖。 保护功能，这将导致AD的疾病进展速度降低和认知能力下降 患者为了验证这一假设，我们将设计和合成有效siRNA的寡核苷酸， INPP 5D的敲除（目标1）。我们将开发一种筛选试验，用于选择寡核苷酸， 最佳击倒效率（目标2）。重要的是，这些寡核苷酸将被修饰以用于有效组织 大脑中的分布和敲除效率，这将允许研究INPP 5D对小胶质细胞的沉默 在AD的5xFAD鼠模型中的活性和相关免疫应答（目的3）。我们强大 这些方法旨在阐明SHIP 1对神经炎症、突触完整性和神经元凋亡的机制影响。 与AD相关的更广泛的神经病理学后遗症。总的来说，这些研究将支持翻译 一种治疗性siRNA进入临床，将减少神经炎症，淀粉样蛋白负担，并改善认知， 从而推进了NIH/NIA开发AD新疗法的使命。

项目成果

Optimal transport- and kernel-based early detection of mild cognitive impairment patients based on magnetic resonance and positron emission tomography images.

• DOI: 10.1186/s13195-021-00915-3
• 发表时间: 2022-01-07
• 期刊: Alzheimer's research & therapy
• 作者: Liu Z;Johnson TS;Shao W;Zhang M;Zhang J;Huang K
• 通讯作者: Huang K

A novel fluorogenic reporter substrate for 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCγ2): Application to high-throughput screening for activators to treat Alzheimer's disease.

• DOI: 10.1016/j.slasd.2023.03.003
• 发表时间: 2023-06
• 期刊: SLAS DISCOVERY
• 影响因子: 3.1
• 作者: Visvanathan, Ramya;Utsuki, Tadanobu;Beck, Daniel E.;Lendy, Emma;Sun, Kuai-lin;Liu, Yinghui;Hering, Kirk W.;Mesecar, Andrew;Zhang, Zhong-Yin;Putt, Karson S.
• 通讯作者: Putt, Karson S.

Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology.

• DOI: 10.1002/trc2.12253
• 发表时间: 2022
• 期刊: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
• 影响因子: 4.8
• 作者: Potjewyd, Frances M;Annor-Gyamfi, Joel K;Aube, Jeffrey;Chu, Shaoyou;Conlon, Ivie L;Frankowski, Kevin J;Guduru, Shiva K R;Hardy, Brian P;Hopkins, Megan D;Kinoshita, Chizuru;Kireev, Dmitri B;Mason, Emily R;Moerk, Charles T;Nwogbo, Felix;Pearce, Kenneth H Jr;Richardson, Timothy I;Rogers, David A;Soni, Disha M;Stashko, Michael;Wang, Xiaodong;Wells, Carrow;Willson, Timothy M;Frye, Stephen V;Young, Jessica E;Axtman, Alison D
• 通讯作者: Axtman, Alison D

AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery.

• DOI: 10.1002/trc2.12246
• 发表时间: 2022
• 期刊: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
• 影响因子: 4.8
• 作者: Potjewyd, Frances M;Annor-Gyamfi, Joel K;Aube, Jeffrey;Chu, Shaoyou;Conlon, Ivie L;Frankowski, Kevin J;Guduru, Shiva K R;Hardy, Brian P;Hopkins, Megan D;Kinoshita, Chizuru;Kireev, Dmitri B;Mason, Emily R;Moerk, Charles T;Nwogbo, Felix;Pearce, Kenneth H;Richardson, Timothy I;Rogers, David A;Soni, Disha M;Stashko, Michael;Wang, Xiaodong;Wells, Carrow;Willson, Timothy M;Frye, Stephen V;Young, Jessica E;Axtman, Alison D
• 通讯作者: Axtman, Alison D

MOGONET integrates multi-omics data using graph convolutional networks allowing patient classification and biomarker identification.

• DOI: 10.1038/s41467-021-23774-w
• 发表时间: 2021-06-08
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wang T;Shao W;Huang Z;Tang H;Zhang J;Ding Z;Huang K
• 通讯作者: Huang K