Identification of molecular pathways contributing to central corneal thickness

描述（由申请人提供）：青光眼是一种复杂且异质性的视神经病变，是美国致盲的主要原因。青光眼的发病机制有多种途径，包括但不限于高眼压、视神经拔火罐和角膜中央厚度过薄。青光眼背后的许多分子通路尚未完全确定。目前治疗青光眼的唯一方法是通过针对IOP通路的方法，这一点很明显。为了在青光眼早期检测机制和替代治疗方面取得进展，需要更彻底地定义青光眼的潜在途径。这可以通过遗传学来完成，通过鉴定与青光眼定量相关的性状的基因。本应用程序的总体目标是确定影响角膜中央厚度（CCT）的分子途径，并将其作为研究青光眼病因的切入点。核心假设是，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确定青光眼相关分子通路的基本原理是，通过使用青光眼单一的、不太复杂的成分，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的功能途径，这将为制定更好的治疗策略和早期发现该疾病奠定基础。为了获得这一应用的总体目标，将通过追求两个特定目标来检验中心假设：1)使用定量遗传学识别调节小鼠CCT的基因；2)确定Cctq1（即角膜中央厚度QTL 1）对青光眼表型的影响程度。在第一个目标下，小鼠7号染色体上调节CCT大小的基因将通过遗传作图、生物信息学和DNA测序来鉴定。在第二个目标下，已经确定的cct调节位点（Cctq1）将使用功能和生理方法测试其对青光眼病理过程中受影响的细胞和组织的影响。这项提议的研究意义重大，因为影响小鼠CCT的基因很可能与影响人类CCT的基因相同。这些知识将为人类青光眼病理生理学的机制提供见解，并最终应用于人类研究。

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.