Retinal dysfunction in Alzheimer's disease mouse models

阿尔茨海默病小鼠模型的视网膜功能障碍

• 批准号: 10289116
• 负责人: Ashay D Bhatwadekar
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289116
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Anatomy; Animal Model; Animals; Apolipoprotein E; Architecture; Area; Astrocytes; Biological Assay; Biological Markers; Blindness; Blood Glucose; Blood Vessels; Blood flow; Brain; Clinical; Collaborations; Color Visions; Communication; Complications of Diabetes Mellitus; Data; Defect; Dementia; Depth Perception; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Disease; Early Diagnosis; Elderly; Electrophysiology (science); Electroretinography; Ensure; Environment; Equilibrium; Evaluation; Exhibits; Eye; Fluorescein Angiography; Foundations; Functional disorder; Future; Genes; Genetic; Genotype; Glaucoma; Goals; Grant; High Fat Diet; Histology; Hyperglycemia; Impaired cognition; Impairment; Institution; Insulin Receptor; Knock-in Mouse; Knowledge; Late Onset Alzheimer Disease; Light; Link; Longitudinal Studies; Memory; Microglia; Microvascular Dysfunction; Mission; Modeling; Molecular; Muller' s cell; Mus; National Eye Institute; National Institute on Aging; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Optic Disk; Optical Coherence Tomography; Pathogenesis; Pathologic; Pathology; Pattern; Phenotype; Play; Positioning Attribute; Potassium; Public Health; Receptor Signaling; Regulation; Research; Research Design; Research Support; Resources; Retina; Retinal Diseases; Retinal Ganglion Cells; Risk; Risk Factors; Role; Series; Signal Transduction; Solid; Structure; Synapses; Testing; Thick; Thinking; Thinness; Vision; Vision Disorders; Water; Work; abeta deposition; age related; apolipoprotein E-4; base; biomarker development; brain tissue; cerebrovascular imaging; cognitive function; density; diabetic; drug development; ganglion cell; genetic risk factor; human old age (65+); macroglia; macular edema; mouse model; neuroimaging; neurotransmission; next generation; novel; object recognition; relating to nervous system; response; retinal angiogenesis; retinal axon; sensor; success; transcriptome; transcriptome sequencing; transcriptomics; treatment response; visual dysfunction; water channel

Project Summary Alzheimer’s disease (AD) is the most common dementia resulting in progressive impairment in memory and thinking and affecting millions of older adults worldwide, with no cure. The eye, as part of the central nervous system, exhibits a range of defects in AD, such as retinal thinning, ganglion cell loss, microvascular deficit and Müller cell dysfunction. The eye provides a transparent window for studying neural and vascular defects, thus can aid in biomarker development in AD. This grant supplement will capitalize on this unique position of the eye in studying pathological aspects of AD with the potential to develop biomarkers for assessment of AD. It builds on the solid foundation of the current R01EY027779, including ocular phenotyping and functional assessment of Kif4.1 channels in Müller cells, but extends the work from diabetic retinopathy into AD. Late-onset AD (LOAD) is the most common form of AD, and genetics plays a critical role in AD pathogenesis, with apolipoprotein e4 (APOE4) as a leading factor. Model Organism Development & Evaluation of Late-Onset Alzheimer’s disease (MODEL-AD) is a consortium that is developing the next generation of mouse models relevant to LOAD and characterizing various phenotypes in these models. We will leverage this unique MODEL- AD resource to study the ocular phenotype in APOE4KI mice (LOAD-risk) in comparison to APOE3KI (LOAD- neutral). Our pragmatic study design will first characterize these mice in a series of visual function assays, explore their retinal transcriptome for markers of neurodegeneration and compare with that of brain tissue, and study Kir4.1 channels in Müller cells, where APOE4 is mainly concentrated. In a second set of studies, we will challenge these mice to high-fat diet treatment to study retinal function in the hyperglycemic milieu and test whether the presence of APOE4 genotype precipitates a diabetic retinopathy (DR) phenotype, the most common complication of diabetes. The above study design is based on our preliminary data which demonstrate a vascular deficit in the brain and increased blood glucose in response to a high-fat diet in APOE4 animal models. To ensure the success of the project, we have gathered a team of experts in both eye and AD research. The research in this supplement will advance the AD research field in a variety of ways: (i) study of retinal vasculature may aid in the early diagnosis of AD; (ii) transcriptomics will identify novel targets altered in AD retinas, which will help in understanding the disease pathogenesis and future drug development; (iii) brain Kir4.1 channels are downregulated in AD; however, how APOE4 affects their function is not known. Our studies will point towards studying mechanisms in this direction; (iv) DR is a blinding eye condition, and AD patients demonstrate a correlation with DR. Our studies will shed light on the link between these two pathologies; (v) our studies will contribute to MODEL-AD’s goal of characterizing the phenotype of AD models and establish a paradigm for ocular assessments of future models.

项目概要 阿尔茨海默病 (AD) 是最常见的痴呆症，会导致记忆力和记忆力进行性损害 思考并影响着全世界数百万老年人，但无法治愈。眼睛，作为中枢神经的一部分 系统，表现出 AD 的一系列缺陷，例如视网膜变薄、神经节细胞损失、微血管缺陷和 米勒细胞功能障碍。眼睛为研究神经和血管缺陷提供了一个透明的窗口，因此 可以帮助 AD 生物标志物的开发。该补助金将利用眼睛的这一独特位置 研究 AD 的病理方面，并有可能开发用于评估 AD 的生物标志物。它构建了 基于当前 R01EY027779 的坚实基础，包括眼表型分析和功能评估 Kif4.1 在 Müller 细胞中发挥作用，但将其作用范围从糖尿病性视网膜病变扩展到 AD。 晚发性 AD (LOAD) 是 AD 最常见的形式，遗传学在 AD 发病机制中起着至关重要的作用， 以载脂蛋白 e4 (APOE4) 作为主导因子。晚发型模型生物体的开发与评估 阿尔茨海默病 (MODEL-AD) 是一个正在开发下一代小鼠模型的联盟 与负载相关并表征这些模型中的各种表型。我们将利用这种独特的模型- AD 资源，用于研究 APOE4KI 小鼠（LOAD-风险）与 APOE3KI（LOAD- 风险）的眼表型 中性的）。我们务实的研究设计将首先通过一系列视觉功能测定来表征这些小鼠， 探索其视网膜转录组中的神经退行性变标志物，并与脑组织的转录组进行比较，以及 研究 Müller 细胞中的 Kir4.1 通道，其中 APOE4 主要集中。在第二组研究中，我们将 对这些小鼠进行高脂肪饮食治疗，以研究高血糖环境中的视网膜功能并进行测试 APOE4 基因型的存在是否会导致最常见的糖尿病视网膜病变 (DR) 表型 糖尿病的并发症。上述研究设计基于我们的初步数据，该数据证明了血管 APOE4 动物模型中高脂肪饮食导致大脑缺陷和血糖升高。为确保 该项目的成功，让我们聚集了一支眼睛和 AD 研究领域的专家团队。 本增刊中的研究将以多种方式推进 AD 研究领域：(i) 视网膜研究 脉管系统可能有助于 AD 的早期诊断； (ii) 转录组学将识别 AD 中改变的新靶标 视网膜，这将有助于了解疾病发病机制和未来的药物开发； (三)脑Kir4.1 AD 中通道被下调；然而，APOE4 如何影响其功能尚不清楚。我们的研究将 指向这个方向的研究机制； (iv) DR 是一种致盲性眼病，AD 患者 证明与 DR 的相关性。我们的研究将揭示这两种病理之间的联系； （五）我们的 研究将有助于 MODEL-AD 的目标，即描述 AD 模型的表型并建立一个 未来模型的视觉评估范例。

项目成果

Effect of the pharmacist-managed cardiovascular risk reduction services on diabetic retinopathy outcome measures.

药剂师管理的降低心血管风险服务对糖尿病视网膜病变结果测量的影响。

• DOI: 10.18549/pharmpract.2019.1.1319
• 发表时间: 2019
• 期刊: Pharmacy practice
• 作者: Weber,ZacharyA;Kaur,Palakpreet;Hundal,Amrita;Ibriga,SomnoomaH;Bhatwadekar,AshayD
• 通讯作者: Bhatwadekar,AshayD

Pharmacist-Managed Diabetic Retinopathy in Hispanic/LatinX Population.

药剂师管理的西班牙/拉丁裔人群糖尿病视网膜病变。

• DOI: 10.1177/08971900221136897
• 发表时间: 2024
• 期刊: Journal of pharmacy practice
• 影响因子: 1.3
• 作者: Patel,Janvi;Gonzalvo,JasmineD;Eckert,GeorgeJ;Schmelz,AndrewN;Bhatwadekar,AshayD
• 通讯作者: Bhatwadekar,AshayD

RNA therapeutics for retinal diseases.

• DOI: 10.1080/14712598.2021.1856365
• 发表时间: 2021-05
• 期刊: Expert opinion on biological therapy
• 影响因子: 4.6
• 作者: Gemayel MC;Bhatwadekar AD;Ciulla T
• 通讯作者: Ciulla T

Circadian rhythm disruption results in visual dysfunction.

• DOI: 10.1096/fba.2021-00125
• 发表时间: 2022-06
• 期刊: FASEB bioAdvances
• 影响因子: 2.7

Anti-integrin therapy for retinovascular diseases.

• DOI: 10.1080/13543784.2020.1795639
• 发表时间: 2020-09
• 期刊: EXPERT OPINION ON INVESTIGATIONAL DRUGS
• 影响因子: 6.1
• 作者: Bhatwadekar, Ashay D.;Kansara, Viral;Luo, Qianyi;Ciulla, Thomas
• 通讯作者: Ciulla, Thomas