Role of cellular memory in glaucoma.

项目摘要/摘要 小梁网纤维化样功能障碍和细胞外基质硬化(TM)是 原发性开角型青光眼的持续性眼压升高。健康TM的短期暴露 细胞对机械损伤导致典型的青光眼样病理，停药后可恢复 侮辱之心。相反，青光眼TM细胞通过储存的机械记忆保持病理表型 尽管培养在软组织样的基质环境中。这项提案的总体目标是确定 TM细胞中的机械记忆是如何首先形成和存储的，以及它是如何促进持久性的 青光眼细胞功能障碍。我们推测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，我们将全面描述TM细胞的机械记忆。单元格 通过机械转导“感觉”它们的机械环境。在目标2中，我们将调查一个 机械调节转录共激活因子YAP在TM细胞调控中的作用 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细胞机械中的作用 记忆力保持。我们将使用我们创新的生物工程原代人类TM细胞包裹的水凝胶 并动态调整矩阵刚度来测试我们的假设。我们的具体目标是： 目的1：探讨机械记忆持续性在青光眼TM细胞功能障碍中的作用。 目的2：确定YAP机械转导在TM细胞机械记忆获得中的作用 和保留力。 目标3：确定表观遗传修饰如何有助于TM细胞的长期机械记忆 留存。

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.