Exosomes and Conventional Outflow Homeostasis

外泌体和常规流出稳态

• 批准号: 10224212
• 负责人: Fiona McDonnell
• 金额: $ 12.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224212
• 关键词: Affect; Anterior; Aqueous Humor; Area; Binding; Biology; Cells; Consequentialism; Cytoskeleton; Elements; Environment; Equilibrium; Extracellular Matrix; Eye; Feedback; Fibronectins; Functional disorder; Gene Expression; Gene Proteins; Genes; Glaucoma; Homeostasis; Human; In Situ; MAP Kinase Gene; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Matrix Metalloproteinases; Mechanics; Mediating; Mentors; MicroRNAs; Molecular Profiling; Monitor; Myosin Light Chains; Outcomes Research; Pathway interactions; Pattern; Perfusion; Phase; Physiologic Intraocular Pressure; Physiological; Play; Process; Production; Proteins; Regulation; Research; Research Personnel; Resistance; Rho-associated kinase; Risk Factors; Role; Signaling Molecule; Stimulus; Stretching; System; Technical Expertise; Therapeutic; Tissues; Trabecular meshwork structure; Tracer; Training; Waste Management; base; career; cell type; differential expression; exosome; extracellular; extracellular vesicles; intercellular communication; kinase inhibitor; mechanotransduction; nanosized; nanovesicle; natural flow; optic nerve disorder; p38 Mitogen Activated Protein Kinase; pressure; repaired; response; transcriptome sequencing

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.

项目摘要 青光眼是一种视神经病变，其中主要危险因素是眼内压（IOP）。 常规流出稳态的失调导致IOP升高。流出的关键要素 稳态是细胞外基质（ECM）的营业额，它也决定了优先流动 穿过组织。实际上，最近有证据表明ECM基因表达差异 小梁网（TM）中低流量和高流量的区域。在癌症中，ECM稳态失调 已证明涉及细胞外纳米层，称为外泌体。外部释放紧密 受调节，并根据其大小，细胞类型特异性功能和 货物。除其他功能外，它们的功能包括废物管理，细胞信号传导和ECM营业额。作为 结果，我们假设从TM细胞释放的外泌体在流出中的ECM中起作用 途径，有助于节段流，并改变了青光眼中的ECM稳态。这项研究旨在 研究外泌体在人类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原代人TM细胞释放的外泌体的影响 并创建从TM Epplants发布的外泌体的全面概况，特别是较低的分析区域 和高流量。在独立阶段，我将研究IOP效应外部释放和调节 在检查如何将外泌体用作的外泌体之前，传统的流出途径 一种改善青光眼功能失调的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 函数（iii）确定外泌体调节的ECM目标，以及（iv）确定外泌体是否可以用于 将ECM稳态标准化。