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.

项目概要 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。 常规流出稳态的失调导致眼压升高。流出稳态的关键要素 是细胞外基质（ECM）的周转率，它也决定了通过细胞的优先流动通道 组织。事实上，最近有证据表明低和高区域之间的 ECM 基因表达存在差异。 小梁网 (TM) 中的血流。在癌症中，ECM 稳态失调已被证明 涉及细胞外纳米囊泡，称为外泌体。外泌体的释放受到严格调控，并且 根据其大小、细胞类型特异性功能和货物与其他纳米囊泡的区别。其中， 它们的功能包括废物管理、细胞间信号传导和 ECM 周转。因此，我们假设 TM 细胞释放的外泌体在流出途径中调理 ECM 中发挥作用，有助于 节段血流，并改变青光眼的 ECM 稳态。本研究旨在调查的作用 外泌体通过人类 TM 细胞和 TM 组织调节 ECM。在独立阶段，我会检查 IOP 如何影响外泌体在传统流出途径中的节段流释放和调节。 接下来，我将使用人类 TM 细胞和 TM 组织，研究如何使用外泌体来改善 青光眼表型和高眼压症。作为这项研究的结果，我们期望 (i) 确定以下角色： 分段流中的外泌体 (ii) 确定 IOP 对外泌体释放和功能的影响 (iii) 识别 ECM 外泌体调节的目标，以及（iv）确定外泌体是否可用于使 ECM 稳态正常化。