Exosomes and Conventional Outflow Homeostasis

项目摘要 青光眼是一种视神经病变，其主要危险因素是眼内压（IOP）升高。 常规流出道稳态失调导致IOP升高。外流的关键要素 稳态是细胞外基质（ECM）的周转，这也决定了优先流动 穿过组织的通道。事实上，最近有证据表明， 小梁网（TM）中的低流量和高流量区域。在癌症中，ECM稳态失调 已经证明涉及细胞外纳米囊泡，称为外来体。外泌体释放紧密地 调节，并且它们基于它们的大小、细胞类型特异性功能和 货物.其中，它们的功能包括废物管理，细胞-细胞信号传导和ECM周转。作为 结果，我们假设TM细胞释放的外泌体在流出的ECM中起调理作用 通路，有助于节段性流动，并改变青光眼中的ECM稳态。本研究旨在 研究外泌体在人TM细胞和TM组织中调节ECM中的作用。在指导期间， 阶段，我将首先检查机械拉伸对从原代人TM细胞释放的外泌体的影响 并创建从TM外植体释放的外泌体的全面概况，特别是低表达区的概况。 高流量。在独立阶段，我将研究IOP如何影响外泌体的释放和调节， 在检查外泌体如何可以被用作 一个改善青光眼中功能失调的ECM稳态的平台。作为这项研究的结果，我们 期望（i）确定外泌体在节段流中的作用（ii）确定IOP对外泌体释放的影响 和功能（iii）鉴定用于外泌体调节的ECM靶，和（iv）确定外泌体是否可用于 使ECM稳态正常化。

Project Summary Glaucoma is an optic neuropathy in which the primary risk factor is elevated intraocular pressure (IOP). Dysregulation of conventional outflow homeostasis results in elevated IOP. Key elements of outflow homeostasis are the turnover of extracellular matrix (ECM), which also determines preferential flow passageways through the tissue. In fact, there is recent evidence of differential ECM gene expression between regions of low and high flow in the trabecular meshwork (TM). In cancer, dysregulation of ECM homeostasis has been demonstrated to involve extracellular nanovesicles, known as exosomes. Exosome release is tightly regulated, and they are differentiated from other nanovesicles based on their size, cell type-specific function and cargo. Amongst others, their functions include waste management, cell-cell signaling and ECM turnover. As a result, we hypothesize that exosomes released from TM cells play a role in opsonizing ECM in the outflow pathway, contributing to segmental flow, and altered ECM homeostasis in glaucoma. This study aims to investigate the role of exosomes in regulating ECM by human TM cells and in TM tissues. During the mentored phase, I will first examine the effect of mechanical stretch on exosomes released from primary human TM cells and create a comprehensive profile of exosomes released from TM explants, specifically profiling regions of low and high flow. During the independent phase, I will examine how IOP effects exosome release and regulation in the conventional outflow pathway in terms of segmental flow before examining how exosomes may be used as a platform to ameliorate the dysfunctional ECM homeostasis in glaucoma. As outcomes of this research we expect to (i) identify a role for exosomes in segmental flow (ii) determine the effect of IOP on exosome release and function (iii) identify ECM targets for exosome regulation and, (iv) ascertain if exosomes can be used to normalize ECM homeostasis.