Identification of molecular pathways contributing to central corneal thickness

描述(申请人提供)：青光眼是一种复杂和异质性的视神经病变，在美国是导致失明的主要原因。青光眼的发病机制有许多途径，包括但不限于高眼压、视神经拔罐和中央角膜厚度变薄。青光眼背后的许多分子途径还没有完全确定。这一点很明显，因为目前治疗青光眼的唯一方法是通过针对眼压途径的方法。为了在开发早期青光眼检测机制和替代疗法方面取得进展，有必要更彻底地定义青光眼的潜在途径。这可以通过识别与青光眼数量相关的特征的基因来通过遗传学来实现。这项应用的总体目标是识别导致中央角膜厚度(CCT)的分子途径，并将其作为研究青光眼病因的切入点。中心假设是，导致薄CCT的一些相同的遗传等位基因和生物学途径也会导致青光眼易感性。使用CCT来确定与青光眼相关的分子通路的基本原理是，通过使用青光眼的单一、不那么复杂的成分，将发现新的青光眼易感基因。因此，这些研究将涉及青光眼发病机制中的功能通路，这将为设计更好的治疗策略和早期发现青光眼奠定基础。为了获得这项应用的总体目标，将通过追求两个特定目标来检验中心假设：1)使用数量遗传学确定调节小鼠CCT的基因；2)确定Cctq1(即中央角膜厚度QTL 1)对青光眼表型的影响程度。在第一个目标下，将使用遗传图谱、生物信息学和DNA测序来识别小鼠7号染色体上调节CCT大小的基因。在第二个目标下，将使用功能和生理方法测试已经识别的CCT调节基因(Cctq1)对青光眼病理过程中受影响的细胞和组织的影响。这项拟议的研究意义重大，因为影响小鼠CCT的基因很可能是那些影响人类CCT的基因。这些知识将提供对可能构成人类青光眼病理生理学基础的机制的洞察，并最终可应用于人类研究。 与公共卫生相关：青光眼是一种可遗传的眼病，导致全球数百万人失明。我们的目标是通过识别调节一个重要的危险因素-中央角膜厚度薄的基因来发现导致青光眼的新的分子途径。这项申请中提出的研究与NIH的任务相关，因为它将导致与青光眼相关的基因的发现，这将催化疾病机制的解体，并最终具有制定预防和/或治疗疾病的策略的能力。

DESCRIPTION (provided by applicant): Glaucoma is a complex and heterogeneous optic neuropathy and is a leading cause of blindness in the United States. Many pathways contribute to glaucoma pathogenesis, including, but not limited to, high intraocular pressure (IOP), optic nerve cupping, and thin central corneal thickness. Many of the molecular pathways that underlie glaucoma are incompletely defined. This is evident in the fact that the only current way of treating glaucoma is through approaches that target the IOP pathway. To make advances in developing earlier glaucoma detection mechanisms and alternative therapeutics, there is a need to more thoroughly define the underlying pathways of glaucoma. This can be accomplished through genetics by identifying the genes of traits that are quantitatively associated with glaucoma. The overall objective of this application is to identify molecular pathways that contribute to central corneal thickness (CCT), using it as an entry point for studying the etiology of glaucoma. The central hypothesis is that some of the same genetic alleles and biological pathways that cause thin CCT also cause glaucoma susceptibility. The rationale for using CCT to determine molecular pathways relevant to glaucoma is that by using a single, less complex component of glaucoma, new glaucoma susceptibility genes will be discovered. These studies will therefore implicate functional pathways in glaucoma pathogenesis, which will lay the groundwork for devising better strategies for treatment and early detection of the disease. To obtain the overall objective of this application, the central hypothesis will be tested by pursuing two specific aims: 1) Identify genes that regulate CCT in mice using quantitative genetics; and 2) Identify the extent to which Cctq1 (i.e., central corneal thickness QTL 1) influences glaucomatous phenotypes. Under the first aim, the gene on mouse chromosome 7 that regulates the magnitude of CCT will be identified using genetic mapping, bioinformatics, and DNA sequencing. Under the second aim, the already identified CCT-regulating locus (Cctq1) will be tested for its influence on cells and tissues that are impacted during glaucoma pathology using functional and physiological approaches. The proposed research is significant because the genes that influence CCT in mice are likely to be those that influence CCT in humans. This knowledge will provide insights into mechanisms that are likely to underlie glaucoma pathophysiology in humans, and that can ultimately be applied to human studies. PUBLIC HEALTH RELEVANCE: Glaucoma is a heritable ocular disease that causes blindness in millions of people worldwide. Our goal is to uncover new molecular pathways that contribute to glaucoma by identifying the genes that regulate an important risk factor, thin central corneal thickness. The research proposed in this application is relevant to NIH's mission because it will lead to the discovery of genes relevant to glaucoma, which will catalyze the unraveling of disease mechanisms, and ultimately, the ability to devise strategies for preventing and/or treating the disease.