Identification of molecular pathways contributing to central corneal thickness

鉴定影响中央角膜厚度的分子途径

• 批准号: 8526467
• 负责人: Demelza Koehn
• 金额: $ 5.77万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526467
• 关键词: Affect; African American; Alleles; Bioinformatics; Biological; Blindness; Cells; Chromosome Mapping; Chromosomes, Human, Pair 7; Clinical; Complex; Cornea; DNA; DNA Sequence; Detection; Disease; Early Diagnosis; Etiology; Family; Functional disorder; Genes; Genetic; Glaucoma; Goals; Heredity; Human; Knowledge; Lead; Link; Measures; Mission; Molecular; Mus; Optic Nerve; Outcome; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiologic Intraocular Pressure; Physiological; Predisposition; Quantitative Genetics; Quantitative Trait Loci; Race; Recording of previous events; Research; Resources; Risk Factors; Severities; Stretching; Susceptibility Gene; Testing; Therapeutic; Thick; Time; Tissues; United States; Visual Fields; Work; blind; gene discovery; high intraocular pressure; insight; optic nerve disorder; prevent; trait; treatment strategy

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.

描述（由申请人提供）：青光眼是一种复杂的异质性视神经病变，是美国致盲的主要原因。许多途径促成青光眼发病机制，包括但不限于高眼内压（IOP）、视神经杯状和薄的中央角膜厚度。许多青光眼的分子通路尚未完全确定。这在以下事实中是显而易见的：目前治疗青光眼的唯一方法是通过靶向IOP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，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实现，即识别与青光眼定量相关的性状基因。本申请的总体目标是确定有助于中央角膜厚度（CCT）的分子途径，将其用作研究青光眼病因的切入点。中心假设是，一些相同的遗传等位基因和生物学途径，导致薄CCT也导致青光眼易感性。使用CCT确定青光眼相关分子通路的基本原理是，通过使用青光眼的单一、不太复杂的组分，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途径，这将为设计更好的治疗策略和早期发现疾病奠定基础。为了获得本申请的总体目标，将通过追求两个具体目标来测试中心假设：1）使用定量遗传学鉴定调节小鼠中CCT的基因;以及2）鉴定Cctq 1（即，中央角膜厚度QTL 1）影响角膜水肿表型。在第一个目标下，将使用遗传作图、生物信息学和DNA测序来鉴定小鼠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确定的CCT调节位点（Cctq 1）对青光眼病理过程中受到影响的细胞和组织的影响。这项研究意义重大，因为影响小鼠CCT的基因很可能是影响人类CCT的基因。这些知识将提供深入了解可能是人类青光眼病理生理学基础的机制，并最终应用于人类研究。