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

• 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
• 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

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.

项目摘要 由小梁的水幽默（AH）引流受损引起的眼内压（IOP） 网眼（TM）被认为是青光眼中的Haveten视神经萎缩和视网膜神经节细胞死亡 患者。通过TM进行AH排水的外部因素或细胞内机制均未有 它们在正常或眼部高血压眼中完全定义。 我们最近的研究表明，生长分化因子15（GDF-15）是TGF-β的遥远成员 细胞因子的超家族是人类TM细胞分泌的细胞外基质（ECM）的常规一致， 响应各种IOP升高剂，表现出强大的上调，并诱导细胞收缩力，α- TM细胞中平滑肌肌动蛋白表达，ECM积累和SMAD激活。此外，啊 源自原发性的开角青光眼（POAG）人类患者在 GDF-15水平相对于来自年龄匹配的白内障受试者的控制AH样品。有趣的是，转基因 过表达人GDF-15的小鼠长期暴露了IOP，短期灌注 带有重组RGDF-15的封闭的小鼠眼睛会导致明显的AH出口变化。这些 有前途和新颖的初步观察使我们在稳态中扮演了GDF-15的关键作用 AH出口和IOP，并假设GDF-15级别的改变破坏了涉及的关键细胞事件 AH通过TM排水，从而影响IOP并参与POAG的病因，这是 被认为是全球失明的主要原因之一。 为了建立对GDF-15如何调节AH出口和IOP的机械和更深入的理解， 调查将以确定的三个特定目的进行：1）。接收器和下游 人类TM细胞中由GDF-15调节的信号通路和细胞特征2）。 GDF-15- 使用靶向和转基因小鼠的基因和组织的介导的AH出口和IOP调节 人眼，3）。调节来自TM细胞中基质商店的活性GDF-15的生物可用性，以及 循环GDF-15作为青光眼患者显着性的生物标志物的可行性评估。 据我们所知，这是对GDF-15（应力反应细胞因子）的首次深入研究 和青光眼，完成（基于细胞和体内啮齿动物和人类研究）的完成 不仅展示了GDF-15在AH出口和IOP中的明确作用，还可以产生有影响力的见解 进入眼高血压的病因，并能够鉴定青光眼的创新治疗方法。