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 青光眼是一种以眼压升高为主要危险因素的视神经病变。 传统的流出平衡失调会导致眼压升高。外流的关键要素 动态平衡是细胞外基质(ECM)的周转，这也决定了优先流 穿过组织的通道。事实上，最近有证据表明，ECM基因在 小梁网(TM)中的低血流和高血流区域。在癌症中，ECM动态平衡失调 已经被证明涉及细胞外纳米囊泡，也就是众所周知的外体。外切体的释放很紧密 它们与其他纳米囊泡的区别在于它们的大小、细胞类型特定的功能和 货物。其中，它们的功能包括废物管理、细胞-细胞信号和ECM周转。作为一名 结果：我们推测TM细胞释放的外切体在细胞外流中起着调节ECM的作用。 途径，促进节段性血流，并改变青光眼的ECM动态平衡。这项研究旨在 研究外切体在调节人TM细胞和TM组织细胞外基质中的作用。在接受指导的过程中 阶段，我将首先研究机械拉伸对原代人类TM细胞释放的外切体的影响 并创建从TM外植体释放的外切体的全面概况，特别是LOW区域的概况 和高流量。在独立阶段，我将研究眼压如何影响外膜的释放和调节。 传统的外流途径，在研究外体如何被用作 一种改善青光眼患者细胞外基质稳态失调的平台。作为这项研究的结果，我们 期望(I)确定外切体在节段性血流中的作用(Ii)确定眼压对外切体释放的影响 和功能(Iii)确定外切体调节的ECM靶点，以及(Iv)确定外切体是否可用于 使ECM动态平衡正常化。