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

项目总结 通过小梁的房水引流受损引起的高眼压 研究发现，NetWork(TM)可加速青光眼患者的视神经萎缩和视网膜神经节细胞死亡 病人。无论是外部因素还是细胞内调节通过TM的AH排放的机制都没有 在正常或高眼压的眼睛中被完全定义。 我们最近的研究发现，生长分化因子-15(GDF15)是转化生长因子-β的远亲成员 细胞因子超家族，是人TM细胞分泌的细胞外基质(ECM)的常规成分， 对各种眼压升高药物表现出强劲的上调作用，并诱导细胞收缩，α- TM细胞中平滑肌肌动蛋白的表达、ECM积聚和SMAD激活。此外，AH 源于原发性开角型青光眼(POAG)的人类患者表现出显著的增加(~6倍) 年龄匹配的白内障患者的对照AH样本的GDF-15水平。有趣的是，转基因 过量表达人GDF-15的小鼠表现出慢性高眼压，短期灌流 用重组rGDF-15摘除小鼠眼可引起明显的AH流出改变。这些 有希望的和新颖的初步观察使我们得出结论，GDF-15在体内平衡中起关键作用。 AH外流和眼压，并假设GDF-15水平的变化扰乱了参与 通过TM引流，从而影响眼压，参与POAG的病因，这是 被认为是全球导致失明的主要原因之一。 为了从机制上更深入地了解GDF-15是如何调节AH流出和眼压的， 调查将在三个具体目标下进行，以确定：1)。受体及其下游 GDF-15对人TM细胞的信号转导途径及细胞特性的调控，2)。GDF-15- 基因靶向转基因小鼠和培养器官对眼压和眼压的调节作用 人眼，3)。TM细胞基质中活性GDF-15生物利用度的调节，以及 循环GDF-15作为青光眼患者有意义的生物标志物的可行性评估。 据我们所知，这是第一次深入研究GDF-15，一种应激反应细胞因子，在TM 和青光眼，完成(基于细胞的和活体的啮齿动物和人类研究) 不仅展示了GDF-15在AH流出和眼压中的决定性作用，而且还产生了有影响力的见解 研究高眼压的病因，并能够确定青光眼的创新治疗方法。

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.