Molecular Genetics of Norma Tension Glaucoma

描述（由申请人提供）：青光眼是一种常见的视神经疾病，影响全球超过6000万人，是美国失明和视力残疾的主要原因。然而，导致青光眼的生物学途径尚未得到很好的理解，这阻碍了早期检测和治疗这种疾病的努力。 因此，非常需要在分子水平上阐明青光眼的原因。我们鉴定了一个新的青光眼基因，TANK结合激酶1（TBK 1），并发现TBK 1基因的重复与青光眼相关。TBK 1已在非眼组织中被广泛研究，并在先天免疫系统中具有明确的作用。活化的TBK 1刺激吞噬体的组装和细菌、蛋白质和细胞器的吞噬/消除（称为自噬的过程）。三个自噬基因（TBK 1，OPTN和TLR 4）编码相互作用的蛋白质，也被描述为NTG基因。此外，在青光眼的实验动物模型中，自噬与视网膜神经节细胞死亡有关。我们发现TBK 1是NTG基因，这为自噬在NTG的发病机制中起重要作用提供了额外的证据。来自NTG的人类遗传学研究和来自实验性青光眼模型系统的数据的会聚提供了强有力的证据，即自噬可能是青光眼中视网膜神经节细胞死亡的发病机制中的中心过程。我们的中心假设是TBK 1影响青光眼病理学关键部位的自噬，即形成视神经的视网膜神经节细胞。该途径的失调（例如通过TBK 1的复制）可能启动导致视网膜神经节细胞凋亡、视力丧失和青光眼的级联事件。我们建议用三个特定的目标来测试我们的假设，这些目标使用我们独特而强大的青光眼患者队列，人类供体眼睛和具有与人类患者相同遗传缺陷的转基因TBK 1小鼠。我们将通过使用下一代DNA测序策略测试大群青光眼患者的自噬基因突变来确定导致青光眼的新基因。我们将确定TBK 1突变（基因重复）对转基因TBK 1小鼠（我们已经制造并准备研究）视网膜中青光眼发展和自噬激活的影响。我们还将测试刺激或阻断自噬的药物是否有能力预防这些小鼠的青光眼。我们将通过鉴定视网膜中相互作用的蛋白质来研究TBK 1缺陷导致青光眼的途径。通过这些实验，我们将开始表征TBK 1基因缺陷导致青光眼的生物学途径，验证青光眼的动物模型，并开始将我们的发现转化为诊断和治疗疾病的新方法。

DESCRIPTION (provided by applicant): Glaucoma is a common disease of the optic nerve that affects over 60 million people worldwide and is a leading cause of blindness and visual disability in the United States. However, the biological pathways that lead to glaucoma are not well understood, and this has hindered efforts for early detection and treatment of this condition. Consequently, there is great need to clarify the causes of glaucoma at the molecular level. We identified a new glaucoma gene, TANK binding kinase 1 (TBK1) and discovered that duplication of the TBK1 gene is associated glaucoma. TBK1 has been studied extensively in non-ocular tissues and has well- defined roles in the innate immune system. Activated TBK1 stimulates assembly of a phagosome and engulfment / elimination of bacteria, proteins, and organelles (a process known as autophagy). Three autophagy genes (TBK1, OPTN, and TLR4) encode interacting proteins and have also been described as NTG genes. Moreover, autophagy has been implicated in the retinal ganglion cell death in experimental animal models of glaucoma. Our discovery that TBK1 is an NTG gene provides additional evidence that autophagy has an important role in the pathogenesis of NTG. The convergence of data from human genetic studies of NTG and from experimental glaucoma model systems provides strong evidence that autophagy may be a central process in the pathogenesis of retinal ganglion cell death in glaucoma. Our central hypothesis is that TBK1 influences autophagy at the key site of pathology in glaucoma, the retinal ganglion cells that form the optic nerve. Dysregulation of this pathway (e.g. by duplication of TBK1) may start a cascade of events that leads to apoptosis of the retinal ganglion cells, vision loss, and glaucoma. We propose to test our hypothesis with three specific aims that use our unique and powerful collection of glaucoma patient cohorts, human donor eyes, and transgenic TBK1 mice that have the same genetic defect as human patients. We will identify new genes that cause glaucoma by testing large cohorts of glaucoma patients for mutations in autophagy genes using next generation DNA sequencing strategies. We will determine the effect of TBK1 mutation (gene duplication) on the development of glaucoma and activation of autophagy in the retina of transgenic TBK1 mice (which we have made and are ready to study). We will also test drugs that stimulate or block autophagy for their ability to prevent glaucoma in these mice. We will investigate the pathway(s) by which TBK1 defects lead to glaucoma by identifying interacting proteins in the retina. With these experiments, we will begin to characterize the biological pathway by which defects in the TBK1 gene lead to glaucoma, validate an animal model of glaucoma, and begin to translate our discoveries into new approaches to diagnosis and treatment of disease.