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.

抽象的 阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，导致痴呆症的大部分 在世界范围内，除了认知缺陷之外，视觉功能障碍在 AD 中也很常见，并且可能是由于病理原因造成的。 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糖尿病已被确定为重要的疾病。 我们最近在流行病学研究和临床试验中发现了一种新的 AD 危险因素和合并症。 NLRP3-NLRC4双重炎性体可能有助于神经病理学在这项研究中，我们将实现。 评估 AD 并发 DM 对认知、视力和认知能力的影响的补充目标 此外，使用临床前小分子抑制剂，我们将确定 NLRP3-NLRC4 炎性体双重抑制对 AD 模型视觉和认知读数的功效 我们建议通过测试单独和双重炎症小体来解决这一差距。 我们发现双重炎性体抑制优于单独抑制。 炎症小体抑制可预防 DM/AD 小鼠的视觉功能障碍和认知障碍。 这些研究结合起来将阐明 DM/AD 是否会恶化视网膜和大脑病变，并确定 解决这些复杂而普遍的病症的潜在治疗策略。

项目成果

Subretinal injection in mice to study retinal physiology and disease.

对小鼠进行视网膜下注射以研究视网膜生理学和疾病。

• 发表时间: 2022-06
• 影响因子: 14.8
• 作者: Huang, Peirong;Narendran, Siddharth;Pereira, Felipe;Fukuda, Shinichi;Nagasaka, Yosuke;Apicella, Ivana;Yerramothu, Praveen;Marion, Kenneth M;Cai, Xiaoyu;Sadda, Srinivas R;Gelfand, Bradley D;Ambati, Jayakrishna
• 通讯作者: Ambati, Jayakrishna

Voluntary Exercise Suppresses Choroidal Neovascularization in Mice.

自愿运动抑制小鼠脉络膜新生血管形成。

• 发表时间: 2020-05-11
• 影响因子: 4.4
• 作者: Makin, Ryan D;Argyle, Dionne;Hirahara, Shuichiro;Nagasaka, Yosuke;Zhang, Mei;Yan, Zhen;Kerur, Nagaraj;Ambati, Jayakrishna;Gelfand, Bradley D
• 通讯作者: Gelfand, Bradley D

Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19.

因 COVID-19 住院的美国退伍军人使用羟氯喹的结果。

• 发表时间: 2020
• 作者: Magagnoli, Joseph;Narendran, Siddharth;Pereira, Felipe;Cummings, Tammy H;Hardin, James W;Sutton, S Scott;Ambati, Jayakrishna
• 通讯作者: Ambati, Jayakrishna

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

DDX17 是逆转录转座子 RNA 激活无菌 NLRC4 炎性体的重要介质。

• 发表时间: 2021-12-03
• 影响因子: 24.8
• 作者: Wang, Shao;Narendran, Siddharth;Hirahara, Shuichiro;Varshney, Akhil;Pereira, Felipe;Apicella, Ivana;Ambati, Meenakshi;Ambati, Vidya L;Yerramothu, Praveen;Ambati, Kameshwari;Nagasaka, Yosuke;Argyle, Dionne;Huang, Peirong;Baker, Kirstie L
• 通讯作者: Baker, Kirstie L

Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration.

鉴定氟西汀作为治疗萎缩性黄斑变性的直接 NLRP3 抑制剂。

• 发表时间: 2021
• 影响因子: 11.1
• 作者: Ambati, Meenakshi;Apicella, Ivana;Wang, Shao;Narendran, Siddharth;Leung, Hannah;Pereira, Felipe;Nagasaka, Yosuke;Huang, Peirong;Varshney, Akhil;Baker, Kirstie L;Marion, Kenneth M;Shadmehr, Mehrdad;Stains, Cliff I;Werner, Brian C;Sadda, S
• 通讯作者: Sadda, S