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Role of cellular memory in glaucoma.

细胞记忆在青光眼中的作用。

基本信息

批准号：
10501318
负责人：
Samuel Herberg
金额：
$ 40.75万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10501318
关键词：
ATAC-seq Actins Actomyosin Adopted Aqueous Humor Behavior Binding Biological Models Biomedical Engineering Biophysics Cells ChIP-seq Characteristics Chromatin Coupling Data Disease Dose Encapsulated Environment Epigenetic Process Excision Extracellular Matrix Failure Focal Adhesions Functional disorder Future Gene Expression Genetic Genetic Transcription Glaucoma HDAC1 gene Health Histone Acetylation Histones Human Hydrogels Hyperactivity In Situ Link Mechanics Memory Methylation Modification Morphology Nuclear Nuclear Matrix Nuclear Protein Pathologic Pathology Pharmacology Phenotype Physical condensation Physiologic Intraocular Pressure Physiological Play Polymers Primary Open Angle Glaucoma Proteins Recording of previous events Resistance Role Signaling Protein Testing Time Tissues Trabecular meshwork structure Transcription Coactivator Vision Work chromatin remodeling enzyme activity epigenomics experimental study genome-wide innovation mechanotransduction memory acquisition memory retention novel therapeutic intervention novel therapeutics soft tissue stressor transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Fibrotic-like dysfunction and extracellular matrix stiffening of the trabecular meshwork (TM) is a hallmark of persistent intraocular pressure elevation in primary open-angle glaucoma. Short-term exposure of healthy TM cells to mechanical insult induces characteristic glaucoma-like pathology, which is recoverable after cessation of insult. In contrast, glaucomatous TM cells retain a pathologic phenotype via a stored mechanical memory despite culture within a soft tissue-like matrix environment. The overall objective of this proposal is to identify how mechanical memory in TM cells is first formed and then stored, and how it contributes to the persistence of glaucomatous cellular dysfunction. We hypothesize that TM cell mechanical memory plays a central role in persistent tissue failure in glaucoma. In Aim 1, we will fully characterize TM cell mechanical memory. Cells “sense” their mechanical environment through mechanotransduction. In Aim 2, we will investigate the role of a key mechanoregulatory transcriptional co-activator Yes-associated protein (YAP) in modulating TM cell mechanical memory. Cells “store” mechanical memory through chromatin remodeling and epigenetic modifications. In Aim 3, we will investigate the role of epigenetic modifications in long-term TM cell mechanical memory retention. We will use our innovative bioengineered primary human TM cell-encapsulated hydrogel and dynamically tune matrix stiffness to test our hypothesis. Our specific aims are: Aim 1: To determine how mechanical memory persistence contributes to glaucomatous TM cell dysfunction. Aim 2: To determine how YAP mechanotransduction contributes to TM cell mechanical memory acquisition and retention. Aim 3: To determine how epigenetic modifications contribute to long-term TM cell mechanical memory retention.

项目总结/文摘