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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：
10707119
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/10707119
关键词：
Actins Actomyosin Adopted Aqueous Humor Behavior Binding Biological Models Biomedical Engineering Biophysics Cells Characteristics Chromatin Coupling Cytoskeleton 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 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 permissiveness pharmacologic 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/摘要小梁网（TM）的纤维化样功能障碍和细胞外基质硬化是骨小梁炎的标志。原发性开角型青光眼持续性眼内压升高短期接触健康TM 细胞对机械损伤诱导特征性的类肉瘤病理学，其在停止后可恢复侮辱。相反，昏迷的TM细胞通过储存的机械记忆保留病理表型尽管在软组织样基质环境中培养。本建议的总体目标是确定 TM细胞中的机械记忆是如何首先形成然后存储的，以及它如何有助于持久性青光眼细胞功能障碍。我们假设TM细胞的机械记忆在青光眼的持续性组织衰竭。在目标1中，我们将充分表征TM细胞的机械记忆。细胞 “感觉”他们的机械环境通过机械转导。在目标2中，我们将研究调控TM细胞关键机械调节转录辅激活因子Yes相关蛋白（雅普）机械记忆细胞通过染色质重塑和表观遗传“储存”机械记忆修改.在目标3中，我们将研究表观遗传修饰在长期TM细胞机械损伤中的作用。记忆力我们将使用我们创新的生物工程原代人类TM细胞封装水凝胶并动态调整矩阵刚度来验证我们的假设。我们的具体目标是：目的1：确定机械记忆持续性如何导致昏迷性TM细胞功能障碍。目的2：研究雅普机械信号转导对TM细胞机械记忆获得的影响和保留。目的3：确定表观遗传修饰如何促进TM细胞的长期机械记忆潴留