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

描述（由申请人提供）：这是加州大学伯克利分校视光学院临床科学家Ravi Metlapally博士的一份指导临床科学家研究职业发展奖（K08）申请。他的长期目标是成为一名富有成效的独立临床科学家，为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。他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。这项申请的目的是将他目前所学的技能结合起来，同时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），为他实现这一目标做好准备。这是一份全面的提案，充分利用加州大学伯克利分校刺激而丰富的学术环境，并在各自领域的领导者导师的指导下，精心设计了职业发展计划。计划中的研究明确地解决了一个公共健康问题，国家眼科咨询委员会为国家眼科研究所撰写的报告断言，这个问题值得研究经费。近视对社会经济的影响是巨大的。它影响了超过三分之一的美国成年人，高度/病理性近视是世界上法定失明的主要原因之一。近视的眼轴伸长是由细胞外基质重塑和巩膜变薄促进的。我们的长期目标是了解参与巩膜重塑的分子机制，并制定策略来维持或改善巩膜对眼伸长的抵抗。本提案的具体目的是确定和研究可能参与眼部生长的巩膜中的新调节因子。众所周知，微rna （miRNAs）是信号网络的节点，并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mirna，其中一些在调节细胞外基质重塑和眼部生长调节的关键基因中发挥积极作用。这项研究的基本原理是，一旦知道了mirna如何调节巩膜基因表达，特定的mirna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表达谱，并研究活跃眼生长过程中的差异表达。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靶点。最后，我们将研究在巩膜细胞外基质重塑的背景下，选定的mirna对基因表达的具体影响。提议的工作是新颖和创新的。我们期望所提出的研究将为涉及mirna的更深入的机制研究建立一个强大的平台，并将建立一些潜在的操纵眼睛生长的巩膜靶点。

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.