Diversity Supplement_Torres

摘要 青光眼是世界范围内导致失明的主要原因，也是一个重大的公共卫生问题。在美国，它影响着 超过270万人，到2050年，其患病率将上升到730万。需要靶向治疗来 预防或延缓青光眼的发展。一个主要的危险因素是高眼压，通常是由于 房水流出受损(AQH)。然而，人们对涉及的基因和途径知之甚少。 我们已鉴定编码转录因子GLIS1的GLIS1是原发性开放性肺炎的易感基因。 研究表明，GLIS1-/-小鼠具有青光眼的病理生理特征。我们 还发现GLIS1主要在小梁网络(TM)中表达，小梁网络是 眼部引流组织调节AQH流出，GLIS1-/-小鼠表现出进行性TM变性， 导致高眼压和青光眼视神经病变--强调该模型与研究的相关性 青光眼的症状。我们的初步功能基因组分析表明，GLIS1与GLIS3相互作用， FOXC1是先前被认为与高眼压有关的转录因子，调节TM细胞中的基因表达。 此外，GLIS1活性降低或增加都会损害眼部引流组织的完整性。使用唯一 小鼠模型，遗传和功能基因组方法，以及体外分析，我们建议表征 依赖GLIS1的转录调控网络及其在动态平衡和功能障碍中的作用 眼部引流组织。在目标1中，我们将检验GLIS1表达增加有助于 POAG相关眼部引流组织缺陷并确定POAG相关变异体是否 在GLIS1增强子区域发现可增加其在原代人TM细胞中的转录活性。我们会 还要测试GLIS1在小鼠TM中的过度表达是否会导致高眼压和眼部引流组织缺陷 类似于POAG的情况。最后，我们将评估地塞米松和转化生长因子β2的潜在作用。 与眼压升高有关，作为GLIS1的上游调节因子。在目标2中，我们将测试潜在的基因 GLIS1与Foxc1和/或GLIS3在眼引流组织动态平衡中的相互作用我们将决定 GLIS1和Foxc1或GLIS1和GLIS3杂合子小鼠是否会发生TM缺陷和 改变了眼压调节。同时，我们将描述转录程序和分子途径。 与TM的维护和功能有关。这些研究将为眼科的研究提供重要的机制洞察。 引流组织的动态平衡和功能障碍，并可能揭示治疗青光眼的目标。

ABSTRACT Glaucoma, a major cause of blindness worldwide, is a significant public health concern. In the U.S., it affects over 2.7 million people and its prevalence will rise to 7.3 million by 2050. Targeted therapies are needed to prevent glaucoma or slow its progression. A major risk factor is high intraocular pressure (IOP), typically due to impaired aqueous humor (AqH) outflow. However, the genes and pathways involved are poorly understood. We have identified GLIS1, encoding the transcription factor GLIS1, as a susceptibility gene for primary open- angle glaucoma (POAG) and showed that Glis1–/– mice have pathophysiological hallmarks of glaucoma. We also found that Glis1 is predominantly expressed in the trabecular meshwork (TM), a key component of the ocular drainage tissue regulating AqH outflow, and that Glis1–/– mice exhibit progressive TM degeneration, leading to high IOP, and glaucomatous optic neuropathy—highlighting the relevance of this model for studies of glaucoma. Our preliminary functional genomic analysis suggested that GLIS1 interacts with GLIS3 and FOXC1, transcription factors previously implicated in elevated IOP, to regulate gene expression in TM cells. Moreover, reduced or increased GLIS1 activity can impair the integrity of ocular drainage tissues. Using unique mouse models, genetic and functional genomic approaches, and in vitro assays, we propose to characterize the GLIS1-dependent transcriptional regulatory network and determine its role in homeostasis and dysfunction of ocular drainage tissue. In Aim 1, we will test the hypothesis that increased GLIS1 expression contributes to POAG-associated ocular drainage tissue defects and determine whether the POAG-associated variants we identified in GLIS1 enhancer regions increased its transcriptional activity in primary human TM cells. We will also test whether GLIS1 overexpression in the mouse TM leads to high IOP and ocular drainage tissue defects similar to those in POAG. Finally, we will assess the potential role of dexamethasone and TGFβ2, previously implicated in IOP elevation, as upstream regulators of GLIS1. In Aim 2, we will test for potential genetic interactions between Glis1 and Foxc1 and/or Glis3 in ocular drainage tissue homeostasis. We will determine whether mice heterozygous for null alleles of both Glis1 and Foxc1 or Glis1 and Glis3 develop TM defects and altered IOP regulation. In parallel, we will characterize the transcriptional program and molecular pathways implicated in TM maintenance and function. These studies will provide important mechanistic insight into ocular drainage tissue homeostasis and dysfunction and could reveal targets for therapies to manage glaucoma.