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。外流动态平衡的关键因素 是细胞外基质(ECM)的周转，这也决定了优先通过 组织。事实上，最近有证据表明，ecm基因在低表达区域和高表达区域之间存在差异。 小梁内的流动(TM)。在癌症中，ECM动态平衡的失调已被证明 包括细胞外纳米囊泡，也就是外体。外切体的释放受到严格的监管，而且它们 根据其大小、特定细胞类型的功能和载物区别于其他纳米囊泡。其中， 它们的功能包括废物管理、细胞-细胞信号和ECM周转。因此，我们假设 TM细胞释放的外切体在细胞外流途径中发挥调理ECM的作用， 导致节段性血流，改变了青光眼的细胞外基质稳态。本研究的目的是探讨在人类免疫系统中 Exosome在调节人TM细胞和TM组织细胞外基质中的作用在独立阶段，我将审查 根据节段性血流，眼压如何影响传统流出途径中的外体释放和调节。 接下来，使用人类TM细胞和TM组织，我将研究如何使用外切体来改善 青光眼表型和高眼压。作为本次研究的结果，我们希望(I)确定以下角色 节段性血流中的外切体(II)确定眼压对外切体释放和功能的影响(III)识别细胞外基质 外切体调节的靶点，以及(Iv)确定外切体是否可用于使ECM动态平衡正常化。