Mechanisms of Ocular Morphogenesis The anterior segment

说明（申请人提供）： 眼前节是影响许多疾病的重要因素， the eye.在这些疾病中最常见的是青光眼， 通常与眼内压相关的神经病。在联合 在美国，青光眼是第二大致盲原因，在非洲 美国人因此，了解导致青光眼的机制是 这对于早期发现和有效治疗这种渐进性疾病至关重要 和使人衰弱的疾病。最近，我们已经确定， LIM-homeodomain转录因子LMX 1B引起的先天性疾病 指甲髌骨综合征这种疾病会影响四肢的发育， 导致肾衰竭和早发性开角型青光眼。这一见解 使我们开始研究潜在的分子和遗传学 导致先天性青光眼的机制。通过研究 人LMX 1B，我们已经确定lmx 1b表达于 调节眼内压的组织的发育，将lmx 1b与 眼睛发育和疾病。lmx 1b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 lmx 1b不仅在眼睛发育过程中表达，而且在眼睛发育过程中也高度表达。 在成人角膜、小梁网和虹膜中表达，表明 lmx 1b可能在这些组织中具有重要的功能。为了验证假设 lmx 1b在颅间充质的一个亚群中表达， 波峰，并要求在该组织中，我们将采用条件基因的方法， 在小鼠中的靶向。我们将扩展这些研究，以检验以下假设： lmx 1b是成年小鼠小梁网形成所必需的， lmx 1b在成人中起调节角膜和 小梁网功能使用这些条件工程改造的lmx 1b突变体 小鼠，我们将探索伴随的形态和分子变化， 眼组织中LMX 1B的选择性失活。这些研究将 丰富了我们对有助于眼的分子机制的理解， 人类疾病，尤其是青光眼。此外，这些研究表明， 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.