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

巩膜中的 Micro-RNA：在眼睛生长中的作用及其对近视的影响

• 批准号: 8354400
• 负责人: Ravikanth Metlapally
• 金额: $ 16.54万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354400
• 关键词: Address; Adult; Affect; Animals; Apoptosis; Area; Bioinformatics; Biological Assay; Biomedical Engineering; Biometry; Bioreactors; Bruch' s basal membrane structure; Cell Proliferation; Choroid; Clinical; Collagen; Data; Development; Development Plans; Disease; Environment; Epigenetic Process; Etiology; Extracellular Matrix; Eye; Eye diseases; Fibroblasts; Functional RNA; Funding; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genetic Variation; Genome; Goals; Growth; Human; Investigation; K-Series Research Career Programs; Legal Blindness; Luciferases; Mentors; Messenger RNA; Metabolism; MicroRNAs; Microarray Analysis; Molecular; Molecular Genetics; Molecular Profiling; Molecular and Cellular Biology; Myopia; National Eye Institute; Neural Retina; Optometry; Pathologic; Pathway interactions; Pattern; Phenotype; Play; Population; Predisposition; Preparation; Prevalence; Prevention strategy; Public Health; Regulation; Reporter; Reporting; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Schools; Scientist; Sclera; Signal Transduction; Societies; Structure of retinal pigment epithelium; Testing; Therapeutic; Tissues; Training; Work; base; career development; cost; design; economic impact; effective therapy; fetal; follow-up; genome-wide; human population study; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; new therapeutic target; novel; prevent; skills; socioeconomics; tissue/cell culture; tool; treatment strategy; vision science

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. PUBLIC HEALTH RELEVANCE: Myopia is the most common eye disorder with a high societal cost. The ultimate goal behind understanding myopia development is to design therapeutic strategies to prevent axial elongation of the eye, and therefore myopia progression and/or development. The current proposal aims to study the role of scleral (outer coat of the eye) microRNAs, which are small non-coding RNAs with major roles in disease, during accelerated eye growth. This study will reveal novel therapeutic targets and form a strong platform for specific mechanistic/ functional investigations related to myopia development leading to future prevention strategies.

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博士的指导临床科学家研究职业发展奖（K 08）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，是视觉科学研究。Metlapally博士的兴趣和培训在于临床验光，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。此应用程序的目的是统一的技能，从hi培训到目前为止，沿着获得额外的相关培训（在生物统计学/生物信息学生物工程，和临床验光），这将准备他实现这一目标。这是一个全面的建议，充分利用了加州大学伯克利分校的刺激和丰富的学术环境，并在各自领域的领导者，有成就的导师下精心设计的职业发展计划。计划中的研究清楚地解决了一个公共卫生问题，国家眼科咨询理事会为国家眼科研究所编写的报告声称，这个问题值得研究资助。 近视对我们社会的社会经济影响是巨大的。它影响超过三分之一的美国成年人口，高度/病理性近视是世界上法律的失明的主要原因之一。细胞外基质重塑和巩膜变薄促进近视眼眼轴延长。我们的长期目标是了解参与巩膜重塑的分子机制，并设计策略来维持或改善巩膜对眼延长的抵抗力。这项建议的具体目标是确定和研究巩膜中可能参与眼生长的新调节剂。已知微小RNA（miRNAs）作为信号网络的节点，并通过基因调控影响正常和疾病状态中的许多功能，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）是巩膜，像大多数组织一样，表达miRNA，其中一些在调节细胞外基质重塑和眼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miRNAs如何调节巩膜基因表达，特定的miRNAs就可以作为潜在的靶点来改善巩膜强度，并预防近视的进展和/或发展。首先，我们将建立人类巩膜micro-RNA表达谱，并研究活跃的眼球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micro-RNA谱与相应的全基因组信使RNA谱来确定调控网络和潜在靶点。最后，我们将研究选择的miRNAs对巩膜细胞外基质重塑背景下基因表达的具体影响。所提出的工作是新颖的和创新的。我们期望这些研究将为涉及miRNAs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巩膜靶点来操纵眼球生长。 公共卫生相关性：近视是最常见的眼部疾病，社会成本很高。理解近视发展背后的最终目标是设计治疗策略以防止眼轴伸长，从而防止近视进展和/或发展。目前的提案旨在研究巩膜（眼睛的外层）microRNA的作用，这些microRNA是在疾病中起主要作用的小非编码RNA，在眼睛加速生长期间。这项研究将揭示新的治疗靶点，并为与近视发展相关的特定机制/功能研究形成一个强大的平台，从而制定未来的预防策略。