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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos 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&apos 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

项目摘要

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.

项目摘要阿尔茨海默氏病（AD）是最常见的痴呆，导致记忆和思考和影响全球数百万老年人，无法治愈。眼睛，作为中枢神经的一部分系统，在AD中表现出一系列缺陷，例如残留变薄，神经节细胞损失，微血管缺陷和 müller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中的生物标志物开发。这种赠款补充剂将利用这种独特的眼睛位置在研究AD的病理方面，有可能开发生物标志物来评估AD。它建立在当前R01EY027779的稳固基础上，包括眼表型和功能评估 KIF4.1在Müller细胞中的通道，但将工作从糖尿病性视网膜病变扩展到AD。晚发（负载）是AD的最常见形式，遗传学在AD发病机理中起关键作用，将载脂蛋白E4（APOE4）作为主要因素。模型组织开发和评估晚期阿尔茨海默氏病（AD-AD）是一个正在发展下一代小鼠模型的财团与这些模型中的各种表型相关。我们将利用这种独特的模型 - 与APOE3KI相比中性的）。我们的务实研究设计将首先在一系列视觉功能测定中表征这些小鼠，探索其剩余的转录组，用于神经变性的标记，并与脑组织的记录相比在Müller细胞中研究Kir4.1通道，其中ApoE4主要浓缩。在第二组研究中，我们将向这些小鼠挑战高脂饮食治疗，以研究高血糖环境中的视网膜功能并测试 APOE4基因型的存在是否会沉淀出糖尿病性视网膜病（DR）表型，这是最常见的糖尿病并发症。上述研究设计基于我们的初步数据，该数据证明了血管响应于APOE4动物模型中高脂饮食的大脑不足和血糖增加。确保随着该项目的成功，我们聚集了一支来自眼睛和广告研究的专家团队。该补充的研究将以各种方式推进广告研究领域：（i）剩余的研究脉管系统可能有助于早期诊断AD；（ii）转录组学将确定AD中发生变化的新目标视网膜将有助于理解疾病的发病机理和未来的药物发育；（iii）Brain Kir4.1 渠道在AD中被下调；但是，未知APOE4如何影响其功能。我们的研究将指向朝这个方向研究机制；（iv）DR是一种盲目的眼睛状况，AD患者证明与DR的相关性。我们的研究将阐明这两种病理之间的联系。（v）我们的研究将有助于Model-AD的目标表征AD模型的表型并建立一个对未来模型的眼部评估范式。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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

Anti-integrin therapy for retinovascular diseases.