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Illuminating Glial Dysfunction in Alzheimer’s Disease with Optical Coherence Tomography

利用光学相干断层扫描揭示阿尔茨海默病中的神经胶质功能障碍

基本信息

批准号：
10571184
负责人：
David Philip Bissig
金额：
$ 16.4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571184
关键词：
APP-PS1 Abeta clearance Adult Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amino Acids Amyloid Amyloid beta-Protein Anatomy Antibodies Biological Assay Biology Blood Vessels Brain California Cell Culture Techniques Cells Center for Translational Science Activities Central Nervous System Cerebrospinal Fluid Clinic Clinical Clinical Sciences Clinical Trials Cognitive Dementia Detection Development Diagnosis Diagnostic tests Disease Disease model Elements Fellowship Functional disorder Funding Genetic Genetic Polymorphism Goals Health Human Image Impaired cognition Impairment In Vitro Institution Intercellular Fluid Intervention Knockout Mice Knowledge Light Link Location Measurement Measures Mediating Memory impairment Mentors Methods Modeling Monitor Muller&apos s cell Mus Mutant Strains Mice Neurodegenerative Disorders Neuroglia Neurologist Neurology Neurons Ocular Pathology Optical Coherence Tomography Osmosis Outcome Pathogenesis Pathologic Pathway interactions Patients Persons Photoreceptors Physicians Physiological Physiology Positron-Emission Tomography Production Protein Isoforms Proteins Reporting Research Research Personnel Resources Retina Rodent Role Scientist Senile Plaques Signal Transduction Techniques Technology Testing Training Translating United States National Institutes of Health Universities Vision Water Water Movements abeta accumulation age related aquaporin 4 biomarker development career career development cost diagnostic tool experience fluid flow glymphatic dysfunction glymphatic system imaging modality improved interstitial knockout animal microscopic imaging mild cognitive impairment monomer mouse model next generation non-invasive imaging nonalzheimer dementia novel novel diagnostics novel marker recruit response retinal imaging skills targeted treatment tool translation assay translation to humans translational approach translational neuroscience vision science wasting water channel

项目摘要

PROJECT SUMMARY / ABSTRACT Clearance of amyloid beta (Aβ) is facilitated by glial cells, and impaired Aβ clearance is implicated in the pathogenesis of Alzheimer’s disease (AD). A non-invasive assay of glial function could translate this knowledge into improved health outcomes – leading to the development of new diagnostic tools and/or glia-targeted therapies. Compared to other parts of the central nervous system (CNS), the retina is structurally simple. Within the avascular layers the retina, where the only neuronal elements are photoreceptors, adjacent glia-rich and glia- free layers can inform on glial health. In this project, functional responses to light in those avascular layers of the retina will be monitored with optical coherence tomography (OCT), which is non-invasive and in current widespread clinical use. Responses in the glia-rich and glia-free layers of the retina report on local shifts in water content, which are foundational to glia-mediated waste clearance. For the first Aim of this project, we will compare functional OCT measurements in patients with AD, patients with non-Alzheimer’s dementia, and healthy age- matched adults. We hypothesize that the functional OCT abnormality in AD is disease-specific and is present at early stages of the disease. Positive results would validate a new low-cost, non-invasive, and diagnostically useful marker of AD. The second Aim of this project will use OCT to non-invasively measure retinal glial function in genetic mouse models of disease. Knockout mice lacking the aquaporin 4 protein have impaired glial water and waste clearance. Those mice will be crossed with APP/PS1 mice, a common model of AD based on Aβ overproduction. Functional OCT abnormalities in these mice may be caused by limitations in glial water movement, or by Aβ accumulation, or these features of AD may be synergistic. In vitro OCT of glial cells cultured from those mice will clarify the glial contribution to OCT abnormalities. Positive findings from this Aim would validate OCT as the first clinically-available tool to measure glial function, and provide a direct cell-to-mouse-to- human translational approach for the assessment of glial function in neurodegenerative disease. My career goal is to become an independently-funded physician-scientist studying AD and related dementias. This mentored career development proposal builds upon my clinical experience as a fellowship- trained dementia neurologist, and my research experience in OCT in Alzheimer’s patients as well as (non-OCT) imaging of the rodent retina. The University of California – Davis is the ideal location for the proposed training: The primary mentor will guide me in planning, organizing, and executing funded human research at the institution’s NIA-funded Alzheimer’s Disease Research Center. The team of mentors and collaborators includes experienced NIH-funded vision scientists who will provide training in advanced OCT techniques and Müller glial cell culture. Additional UC Davis training and analytic resources leveraged by this proposal include graduate- level coursework in vision science and the biology of neuroglia, the NIH-funded Clinical and Translational Science Center, and the NIH-funded Mutant Mouse Regional Resource Center.

项目摘要/摘要