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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZEY1)
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Agarwal, Neeraj
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University of California Berkeley
Schools of Optometry/Opht Tech
United States
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Metlapally, Ravikanth; Park, Han Na; Chakraborty, Ranjay et al. (2016) Genome-Wide Scleral Micro- and Messenger-RNA Regulation During Myopia Development in the Mouse. Invest Ophthalmol Vis Sci 57:6089-6097
Shen, Ling; Melles, Ronald B; Metlapally, Ravikanth et al. (2016) The Association of Refractive Error with Glaucoma in a Multiethnic Population. Ophthalmology 123:92-101
Metlapally, Ravi; Wildsoet, Christine F (2015) Scleral Mechanisms Underlying Ocular Growth and Myopia. Prog Mol Biol Transl Sci 134:241-8
Hawthorne, Felicia; Feng, Sheng; Metlapally, Ravikanth et al. (2013) Association mapping of the high-grade myopia MYP3 locus reveals novel candidates UHRF1BP1L, PTPRR, and PPFIA2. Invest Ophthalmol Vis Sci 54:2076-86
Metlapally, Ravikanth; Gonzalez, Pedro; Hawthorne, Felicia A et al. (2013) Scleral micro-RNA signatures in adult and fetal eyes. PLoS One 8:e78984
Young, Terri L; Hawthorne, Felicia; Feng, Sheng et al. (2013) Whole genome expression profiling of normal human fetal and adult ocular tissues. Exp Eye Res 116:265-78