Role of cellular memory in glaucoma.

细胞记忆在青光眼中的作用。

• 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
• 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

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.

项目摘要/摘要 纤维化的功能障碍和小梁网络（TM）的细胞外基质僵硬是一个标志 原发性开角青光眼的持续眼内压升高。健康TM的短期暴露 细胞进行机械侮辱会诱导特征性青光眼样病理，并在停止后可以回收 侮辱。相反，青光眼TM细胞通过存储的机械记忆保留病理表型 尽管在软组织状基质环境中培养。该提议的总体目的是确定 TM细胞中的机械记忆如何首先形成然后存储，以及它如何促进持久性 青光眼细胞功能障碍。我们假设TM细胞机械记忆在 青光眼中持续的组织衰竭。在AIM 1中，我们将充分表征TM细胞机械记忆。细胞 通过机械转导的机械环境“感官”。在AIM 2中，我们将研究一个 调节TM细胞的关键机械调节转录共激活因子相关蛋白（YAP） 机械记忆。通过染色质重塑和表观遗传学的细胞“存储”机械记忆 修改。在AIM 3中，我们将研究表观遗传修饰在长期TM细胞机械中的作用 保留记忆。我们将使用我们的创新生物工程的原代人TM细胞包含的水凝胶 并动态调整矩阵刚度以检验我们的假设。我们的具体目的是： 目标1：确定机械记忆持续性如何有助于青光眼TM细胞功能障碍。 目的2：确定YAP机械转导如何促进TM细胞机械记忆采集 和保留。 目标3：确定表观遗传修饰如何有助于长期TM细胞机械记忆 保留。