Exosomes and Conventional Outflow Homeostasis

外泌体和常规流出稳态

• 批准号: 10039561
• 负责人: Fiona McDonnell
• 金额: $ 12.28万
• 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/10039561
• 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.

项目总结