The Role of GDF-15 in Aqueous Humor Outflow and Glaucoma

GDF-15 在房水流出和青光眼中的作用

基本信息

批准号：
10405620
负责人：
P VASANTHA Rao
金额：
$ 39.04万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405620
关键词：
Activins Address Adhesives Age Aging Apoptosis Aqueous Humor Atrophic Biological Availability Biological Markers Biology Blindness Cataract Cell Death Cell physiology Cells Characteristics Chronic Cues Data Development Diagnosis Disease Distant Drainage procedure Endoplasmic Reticulum Etiology Event Exhibits Extracellular Matrix Eye GDF15 gene Gene Targeting Glaucoma Homeostasis Hour Human Impairment Inflammatory Investigation Knockout Mice Knowledge Mass Spectrum Analysis Matrix Metalloproteinases Mediating Morphology Mus Ocular Hypertension Optic Nerve Organ Oxidative Stress PTK2 gene Pathway interactions Patients Perfusion Phosphotransferases Physiologic Intraocular Pressure Physiology Play Primary Cell Cultures Primary Open Angle Glaucoma Protein-Lysine 6-Oxidase Proteins Proteomics Proto-Oncogene Proteins c-akt Recombinants Regulation Retinal Ganglion Cells Rho-associated kinase Risk Factors Rodent Role Sampling Serum Signal Pathway Smooth Muscle Actin Staining Method Stress Trabecular meshwork structure Transforming Growth Factor beta Transgenic Mice Up-Regulation base biological adaptation to stress cytokine design effective therapy efficacious treatment extracellular in vivo innovation insight member mouse model novel overexpression receptor response senescence targeted treatment

项目摘要

PROJECT SUMMARY Elevated intraocular pressure (IOP) caused by impaired aqueous humor (AH) drainage through the trabecular meshwork (TM) is recognized to hasten optic nerve atrophy and retinal ganglion cell death in glaucoma patients. Neither the external factors nor intracellular mechanisms regulating AH drainage through the TM have been fully defined in normal or ocular hypertensive eyes. Our recent studies revealed that Growth Differentiation Factor-15 (GDF-15), a distant member of the TGF-β superfamily of cytokines, is a regular constituent of the extracellular matrix (ECM) secreted by human TM cells, exhibits robust upregulation in response to various IOP elevating agents, and induces cellular contractility, α- smooth muscle actin expression, ECM accumulation and SMAD activation in TM cells. Furthermore, AH derived from primary open-angle glaucoma (POAG) human patients exhibited a significant increase (~6 fold) in GDF-15 levels relative to control AH samples from age-matched cataract subjects. Interestingly, transgenic mice overexpressing human GDF-15 exhibited chronically elevated IOP, and short-term perfusion of enucleated mouse eyes with recombinant rGDF-15 resulted in significant AH outflow changes. These promising and novel preliminary observations led us to conclude a crucial role for GDF-15 in homeostasis of AH outflow and IOP, and to hypothesize that alterations in GDF-15 levels disrupt key cellular events involved in AH drainage through the TM, thereby impacting IOP and participating in the etiology of POAG, which is considered one of the leading causes of blindness globally. To establish a mechanistic and deeper understanding of how GDF-15 regulates AH outflow and IOP, investigations will be carried out under three specific aims to determine: 1). The receptors and downstream signaling pathways and the cellular characteristics regulated by GDF-15 in human TM cells, 2). GDF-15- mediated regulation of AH outflow and IOP using gene targeted and transgenic mice and organ cultured human eyes, and 3). Regulation of bio-availability of active GDF-15 from stromal stores in TM cells, and feasibility assessment of circulating GDF-15 as a biomarker of significance in glaucoma patients. To the best of our knowledge, this is the first in-depth study on GDF-15, a stress response cytokine, in TM and glaucoma, the completion of which (cell-based and in vivo rodent and human studies) should demonstrate not only the definitive role of GDF-15 in AH outflow and IOP, but also generate impactful insights into the etiology of ocular hypertension and enable identification of innovative treatments for glaucoma.

项目概要由于小梁房水 (AH) 引流受损导致眼压 (IOP) 升高网状结构 (TM) 被认为可加速青光眼中的视神经萎缩和视网膜神经节细胞死亡外部因素和通过 TM 调节 AH 引流的细胞内机制都没有。在正常或高眼压眼中已得到充分定义。我们最近的研究表明，生长分化因子 15 (GDF-15) 是 TGF-β 的远缘成员细胞因子超家族，是人类 TM 细胞分泌的细胞外基质 (ECM) 的常规成分，对各种 IOP 升高剂的反应表现出强烈的上调，并诱导细胞收缩性，α- TM 细胞中平滑肌肌动蛋白表达、ECM 积累和 SMAD 激活。此外，AH 来自原发性开角型青光眼 (POAG) 人类患者的相对于年龄匹配的白内障受试者的对照 AH 样本的 GDF-15 水平。过表达人 GDF-15 的小鼠表现出长期升高的 IOP 和短期灌注使用重组 rGDF-15 的去核小鼠眼睛导致了显着的 AH 流出变化。有前途且新颖的初步观察结果使我们得出结论，GDF-15 在体内稳态中发挥着至关重要的作用。 AH 流出和 IOP，并捕捉 GDF-15 水平的变化破坏参与的关键细胞事件 AH 通过 TM 引流，影响 IOP 并参与 POAG 的病因学，这是被认为是全球失明的主要原因之一。为了更深入地了解 GDF-15 如何调节 AH 流出和 IOP，调查将根据三个具体目标进行，以确定： 1)。人 TM 细胞中 GDF-15 调节的信号通路和细胞特征，2)。使用基因靶向和转基因小鼠和培养的器官介导 AH 流出和 IOP 的调节人眼，以及 3) 调节 TM 细胞基质储存的活性 GDF-15 的生物利用度。循环 GDF-15 作为青光眼患者重要生物标志物的可行性评估。据我们所知，这是对应激反应细胞因子 GDF-15 在 TM 中的首次深入研究和青光眼，其完成（基于细胞和体内啮齿动物和人类研究）应该不仅证明了 GDF-15 在 AH 流出和 IOP 中的决定性作用，而且还产生了有影响力的见解研究高眼压症的病因，并确定青光眼的创新治疗方法。