Exosomes and Conventional Outflow Homeostasis

外泌体和常规流出稳态

• 批准号: 10737784
• 负责人: Fiona McDonnell
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737784
• 关键词: Anterior; Aqueous Humor; Area; Binding; Biology; Cells; Cellular biology; Cornea; Cytoskeleton; Data; Disease; Elements; Environment; Equilibrium; Experimental Designs; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Eye; Feedback; Fibroblasts; Fibronectins; Fibrosis; Flow Cytometry; Functional disorder; Gene Expression; Genes; Glaucoma; Homeostasis; Human; Immunofluorescence Immunologic; In Situ; In Vitro; Integrins; Interruption; Label; Maintenance; Malignant Neoplasms; Matrix Metalloproteinases; Mechanics; Mediating; Mentors; Methods; MicroRNAs; Monitor; Ocular Hypertension; Organ Culture Techniques; Outcomes Research; Pathway interactions; Pattern; Perfusion; Phase; Phenotype; Physiologic Intraocular Pressure; Process; Production; Proteomics; Regulation; Rejuvenation; Research; Resistance; Rho-associated kinase; Risk Factors; Role; Stretching; Techniques; Therapeutic; Tissues; Trabecular meshwork structure; Tracer; Training; Waste Management; cell type; design; differential expression; ex vivo perfusion; exosome; extracellular; extracellular vesicles; intercellular communication; kinase inhibitor; nanosized; nanovesicle; natural flow; novel; optic nerve disorder; repaired; skills; theories

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 meshvvork (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 independent phase, I will examine how IOP effects exosome release and regulation in the conventional outflow pathway in terms of segmental flow. Next, using human TM cells and TM tissues, I will investigate how exosomes can be used to ameliorate a glaucoma phenotype and ocular hypertension. 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。流出道稳态的关键要素 是细胞外基质（ECM）的周转，这也决定了通过血管的优先流动通道。 组织.事实上，最近有证据表明，ECM基因表达的差异区域之间的低和高， 小梁网中的血流（TM）。在癌症中，已经证明ECM稳态的失调， 涉及细胞外纳米囊泡，称为外泌体。外泌体的释放受到严格的调控， 基于它们的大小、细胞类型特异性功能和货物，纳米囊泡与其他纳米囊泡不同。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。因此，我们假设 TM细胞释放的外泌体在流出途径中对ECM起调理作用， 节段性血流，以及青光眼中ECM稳态的改变。本研究旨在探讨 外泌体在调节人TM细胞和TM组织中的ECM中的作用。在独立阶段，我将检查 IOP如何影响节段性流动方面的传统流出途径中的外泌体释放和调节。 接下来，使用人TM细胞和TM组织，我将研究如何使用外泌体来改善TM细胞和TM组织的功能。 青光眼表型和高眼压。作为这项研究的成果，我们希望（i）确定一个角色， （ii）确定IOP对外来体释放和功能的影响（iii）鉴定ECM （iv）确定外泌体是否可用于使ECM稳态正常化。