Visual system and cognitive biology in normal animals versus in an animal model of Alzheimer's disease with or without diabetes treated with solo or dual inflammasome inhibitors

正常动物的视觉系统和认知生物学与单独或双重炎性体抑制剂治疗的患有或不患有糖尿病的阿尔茨海默病动物模型的比较

• 批准号: 10712956
• 负责人: Jayakrishna Ambati
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712956
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Anti-Inflammatory Agents; Biology; Brain Pathology; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complex; Complications of Diabetes Mellitus; Dementia; Diabetes Mellitus; Diabetic Retinopathy; Goals; Hyperglycemia; Hyperinsulinism; Impaired cognition; Inflammasome; Insulin Resistance; Metabolic syndrome; Modeling; Molecular; Mus; Outcome; Pathologic; Pathology; Retina; Risk Factors; Testing; Therapeutic; Vision; Visual; Visual System; comorbidity; efficacy evaluation; efficacy testing; epidemiology study; inhibitor; neurological pathology; novel; pre-clinical; preclinical efficacy; prevent; progressive neurodegeneration; small molecule inhibitor; visual dysfunction

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegeneration that accounts for the majority of dementia worldwide. In addition to cognitive deficits, visual dysfunction is also common in AD and may be due to pathology in the retina. Diabetes mellitus (DM), the metabolic syndrome responsible for diabetic retinopathy, is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance. DM has been identified as a significant risk factor and comorbidity for AD in epidemiological studies and clinical trials. We recently identified a novel dual NLRP3-NLRC4 inflammasome that may contribute to neurologic pathology. In this study, we will achieve complementary goals of evaluating the consequences of AD complicated by DM on cognition, vision, and molecular pathological hallmarks. In addition, using preclinical small molecule inhibitors, we will determine the efficacy of dual NLRP3-NLRC4 inflammasome inhibition on visual and cognitive readouts in AD models in the presence or absence of bona fide DM. We propose to address this gap by testing solo and dual inflammasome inhibitors in models of combined DM/AD. We hypothesize that dual inflammasome inhibition is superior to solo inflammasome inhibition in preventing visual dysfunction and cognitive impairment in DM/AD mice. Together these studies will elucidate whether combined DM/AD exacerbates retinal and brain pathologies, and identify a potential therapeutic strategy to address these complex and prevalent conditions.

摘要 阿尔茨海默病(AD)是一种进行性神经变性，占痴呆的大部分 全世界。除了认知障碍，视觉功能障碍在AD中也很常见，可能是由于病理原因 在视网膜上。糖尿病(DM)是导致糖尿病视网膜病变的代谢综合征， 以高血糖、高胰岛素血症和胰岛素抵抗为特征的。DM已被认为是一个重要的 流行病学研究和临床试验中AD的危险因素和共病。我们最近确定了一部小说 双重NLRP3-NLRC4炎症小体可能参与神经病理。在这项研究中，我们将实现 评估合并糖尿病的AD对认知、视力和 分子病理特征。此外，使用临床前小分子抑制剂，我们将确定 双重NLRP3-NLRC4炎性小体抑制对AD模型大鼠视觉和认知功能的影响 是否存在真正的DM。我们建议通过测试单发炎和双发炎来解决这一差距 糖尿病/阿尔茨海默病模型中的抑制剂。我们假设双重炎性小体抑制优于单独抑制。 炎性小体抑制预防DM/AD小鼠视觉功能障碍和认知功能障碍。同舟共济 这些研究将阐明DM/AD合并是否会加剧视网膜和大脑的病理，并确定 潜在的治疗策略，以解决这些复杂和普遍的情况。

项目成果

DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs.

• DOI: 10.1126/sciimmunol.abi4493
• 发表时间: 2021-12-03
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Wang SB;Narendran S;Hirahara S;Varshney A;Pereira F;Apicella I;Ambati M;Ambati VL;Yerramothu P;Ambati K;Nagasaka Y;Argyle D;Huang P;Baker KL;Marion KM;Gupta K;Liu B;Hinton DR;Canna SW;Sallam T;Sadda SR;Kerur N;Gelfand BD;Ambati J
• 通讯作者: Ambati J

Kamuvudine-9 Protects Retinal Structure and Function in a Novel Model of Experimental Rhegmatogenous Retinal Detachment.

Kamuvudine-9在新型实验性rhegmatogentos视网膜脱离模型中保护视网膜结构和功能。

• DOI: 10.1167/iovs.64.5.3
• 发表时间: 2023-05-01
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4

Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-β induced retinal pigmented epithelium degeneration.

• DOI: 10.1038/s41392-021-00537-z
• 发表时间: 2021-04-14
• 期刊: Signal transduction and targeted therapy
• 影响因子: 39.3
• 作者: Narendran S;Pereira F;Yerramothu P;Apicella I;Wang SB;Ambati K;Hirahara S;Kim Y;Ambati M;Ambati VL;Huang P;Varshney A;Nagasaka Y;Fukuda S;Baker KL;Marion KM;Deussing JM;Sadda SR;Gelfand BD;Ambati J
• 通讯作者: Ambati J

Allopurinol and the Risk of Diabetic Macular Edema among U.S. Veterans with Type 2 Diabetes.

别嘌呤醇与美国 2 型糖尿病退伍军人中糖尿病性黄斑水肿的风险。

• DOI: 10.1080/09273948.2023.2170886
• 发表时间: 2023
• 期刊: Ocular immunology and inflammation
• 影响因子: 3.3
• 作者: Sutton,SScott;Magagnoli,Joseph;Cummings,TammyH;Hardin,JamesW;Ambati,Jayakrishna
• 通讯作者: Ambati,Jayakrishna

Author Reply to Letter to the Editor: In Response to: Comment on Sutton et al.'s "Allopurinol and the Risk of Diabetic Macular Edema among U.S. Veterans with Type 2 Diabetes".

作者对给编辑的信的回复：回应：对 Sutton 等人的“别嘌呤醇与美国 2 型糖尿病退伍军人中糖尿病性黄斑水肿的风险”的评论。

• DOI: 10.1080/09273948.2023.2219326
• 发表时间: 2023
• 期刊: Ocular immunology and inflammation
• 影响因子: 3.3
• 作者: Sutton,SScott;Magagnoli,Joseph;Cummings,TammyH;Hardin,JamesW;Ambati,Jayakrishna
• 通讯作者: Ambati,Jayakrishna