Micro-RNAs in the Sclera: Role in Ocular Growth, and Implications for Myopia

描述(由申请者提供)：这是加州大学伯克利分校验光学院临床科学家拉维·梅特拉帕利博士颁发的临床科学家研究职业发展奖(K08)指导申请书。他的长期目标是成为一名多产的、独立的临床科学家，为促进我们对眼睛生长和近视的理解做出贡献，更广泛地说，为视觉科学研究做出贡献。梅特拉帕利博士的兴趣和培训领域包括临床验光、分子生物学、细胞信号、分子遗传学、表观遗传学和视觉科学的相关领域。这个应用程序的目的是结合到目前为止Hi培训的技能，以及获得额外的相关培训(生物统计学/生物信息学生物工程和临床验光)，使他为实现这一目标做好准备。这是一项全面的建议，充分利用了加州大学伯克利分校激励和丰富的学术环境，在成就卓著的导师的指导下，精心设计了职业发展计划，这些导师都是各自领域的领导者。计划中的研究明确解决了一个公共卫生问题，国家眼科咨询委员会为国家眼科研究所发布的报告断言，这一问题值得研究资助。近视对我们社会的社会经济影响是巨大的。它影响了超过三分之一的美国成年人口，高度/病理性近视是世界上导致法律失明的主要原因之一。近视眼的眼轴延长是由于细胞外基质重塑和巩膜变薄所致。我们的长期目标是了解巩膜重塑的分子机制，并设计出维持或改善巩膜对眼球延长的抵抗力的策略。这项建议的具体目标是确定和研究巩膜中潜在参与眼生长的新的调节因子。MicroRNAs(MiRNAs)被认为是信号网络的节点，通过基因调控影响正常和疾病状态下的许多功能，包括细胞增殖、分化、凋亡和新陈代谢。我们的中心假设(基于我们的初步数据)是，像大多数组织一样，巩膜表达miRNAs，其中一些在调节细胞外基质重塑从而调控眼睛生长的关键基因方面发挥积极作用。这项研究的基本原理是，一旦知道miRNAs如何调节巩膜基因的表达，特定的miRNAs就可以作为潜在的靶点来提高巩膜强度，防止近视的进展和/或发展。首先，我们将建立人类巩膜微RNA的表达谱，并研究在活跃的眼球发育过程中的差异表达。接下来，我们将通过整合和分析巩膜微RNA图谱与相应的全基因组信使RNA图谱来识别调控网络和潜在的靶点。最后，我们将在巩膜外基质重塑的背景下，研究选择的miRNAs对基因表达的特定影响。建议的工作具有新颖性和创新性。我们期望所提出的研究将为涉及miRNAs的更深层次的机制研究建立一个强大的平台，并将建立一些潜在的巩膜靶点来控制眼生长。

DESCRIPTION (provided by applicant): This is a Mentored Clinical Scientist Research Career Development Award (K08) application from Dr. Ravi Metlapally, Clinician Scientist at the UC Berkeley School of Optometry. His long term goal is to become a productive, independent clinician scientist, contributing to the advancement of our understanding of ocular growth and myopia, and more generally, to vision science research. Dr. Metlapally's interests and training lie in clinical optometry, molecular biology, cellular signaling, molecular genetics, epigenetics and related areas in vision science. The purpose of this application is to unite the skills from hi training so far, along with obtaining additional relevant training (in biostatistics/bioinformatics bioengineering, and clinical optometry) that will prepare him to achieve this goal. This is a comprehensive proposal that fully utilizes the stimulating and rich academic environment at UC Berkeley with a thoughtfully designed career development plan under accomplished mentors, who are leaders in their respective fields. The planned studies clearly address a public health issue that the National Advisory Eye Council report for the National Eye Institute asserts is worthy of research funding. The socio-economic impact of myopia on our society is significant. It affects more than one-third of the US adult population, and high/pathologic myopia is one of the major causes of legal blindness in the world. Ocular axial elongation in myopia is facilitated by extracellular matrix remodeling and thinning of the sclera. Our long term goal is to understand the molecular mechanisms involved in scleral remodeling, and to devise strategies to maintain or improve scleral resistance to ocular elongation. The specific objective of this proposal is to identify and study novel regulators in the sclera that are potentially involved in ocular growth. Micro-RNAs (miRNAs) are known to serve as nodes of signaling networks and influence through gene regulation, many functions in both normal and disease states, including cell proliferation, differentiation, apoptosis, and metabolism. Our central hypothesis (based on our preliminary data) is that the sclera, like most tissues, expresses miRNAs, some of which play active roles in modulating genes critical to extracellular matrix remodeling and thus ocular growth regulation. The rationale for the proposed research is that once it is known how miRNAs regulate scleral gene expression, specific miRNAs could serve as potential targets to improve scleral strength, and prevent myopia progression and/or development. First, we will establish human scleral micro-RNA expression profiles, and study differential expression during active ocular growth. Next, we will identify regulatory networks and potential targets by integrating and analyzing scleral micro-RNA profiles with corresponding genome-wide messenger-RNA profiles. Finally, we will investigate the specific effects of select miRNAs on gene expression in the context of scleral extracellular matrix remodeling. The proposed work is novel and innovative. We expect that the proposed studies will set up a strong platform for deeper mechanistic investigations involving miRNAs, and will establish some potential scleral targets for manipulating ocular growth.