Mechanisms of Ocular Morphogenesis The anterior segment

简介(由申请人提供)：发展及功能 眼球前段是影响许多疾病的重要因素。 眼睛。这些疾病中最常见的是青光眼，一种视神经 通常与眼压有关的神经病变。在美国 在许多国家，青光眼是第二大致盲原因，在非洲排名第一 美国人。因此，对导致青光眼的机制的理解是 对于早期发现和有效治疗这种进行性疾病是必不可少的 和衰弱的疾病。最近，我们已经确定了基因的突变 LIM同源结构域转录因子Lmx1b引起先天性疾病 甲膝骨症候群。这种疾病会影响四肢的发育和 结果肾功能衰竭和早发性开角型青光眼。这种洞察力具有 使我们能够开始研究潜在的分子和基因 导致先天性青光眼的机制。通过研究小鼠的同源基因 人类Lmx1b，我们已经确定Lmx1b在表达并需要 调节眼压的组织的发展，将Lmx1b连接到 眼睛发育和疾病。Lmx1b在眼睛中的一个功能可能是 调节细胞外基质的产生。我们还发现， Lmx1b不仅在眼睛发育过程中表达，而且高度表达。 在成人角膜、小梁网和虹膜中表达，表明 Lmx1b在这些组织中可能具有重要的功能。来检验这些假设 Lmx1b在脑间充质的一个子集，即神经细胞中表达 冠，并在需要的组织中，我们将采用条件基因的方法 以小鼠为靶点。我们将扩大这些研究，以检验这一假设 Lmx1b是成年小鼠小梁网形成所必需的 Lmx1b在成人中的作用是调节角膜和 小梁网络函数。使用这些有条件工程的Lmx1b突变体 小鼠，我们将探索伴随着 眼睛组织中Lmx1b的选择性失活。这些研究将 丰富我们对眼部致病分子机制的理解 人类的疾病，尤指青光眼。此外，这些研究将表明 新的诊断和治疗方法用于检测和治疗 青光眼导致的失明。

DESCRIPTION (provided by applicant): The development and the function of the anterior segment of the eye are important factors in many diseases that affect the eye. Among the most common of these diseases is glaucoma, an optic nerve neuropathy that is often associated with intraocular pressure. In the United States, glaucoma is the second leading cause of blindness, first among African Americans. Hence, an understanding of mechanisms that lead to glaucoma are essential to allow early detection and effective treatment of this progressive and debilitating disease. Recently, we have determined that mutations in the LIM-homeodomain transcription factor LMX1B cause a congenital disease caused nail patella syndrome. This disease affects the development of the limbs and results in renal failure and early onset open angle glaucoma. This insight has allowed us to begin to investigate the underlying molecular and genetic mechanisms leading to congenital glaucoma. By studying the mouse ortholog of human LMX1B, we have determined that lmx1b is expressed in and required for development of tissues that regulate intraocular pressure, linking lmx1b to ocular development and disease. One function of lmx1b in the eye may be to regulate the production of the extracellular matrix. We have also found that lmx1b is not only expressed during eye development, but is also highly expressed in the adult cornea, trabecular meshwork, and iris, suggesting that lmx1b may have important functions in these tissues. To test the hypotheses that lmx1b is expressed in a subset of the cranial mesenchyme, the neural crest, and required in that tissue, we will employ methods of conditional gene targeting in mice. We will extend these studies to test the hypothesis that lmx1b is required for trabecular meshwork formation in adult mice and that lmx1b functions in the adult to regulate important aspects of corneal and trabecular meshwork function. Using these conditionally engineered lmx1b mutant mice, we will explore morphological and molecular changes that accompany selective inactivation of lmx1b in tissues of the eye. These studies will enrich our understanding of molecular mechanisms that contribute to ocular diseases in human, especially glaucoma. Furthermore, these studies will suggest novel diagnostic and therapeutic approaches for the detection and treatment of glaucoma-induced blindness.