David Troilo - US grants

DESCRIPTION: A young investigator with a strong background in the study of myopia makes a revised application for experiments in the chicken and in an exciting new primate model - the marmoset - of the development of myopia and the regulation of ocular growth. The experimental design examines specifically the temporal pattern of eye growth in response to visual deprivation in the marmoset, whether the sign of retina defocus guides eye growth in the marmoset, and the role of accommodative control in the regulation of eye growth in both chickens and marmosets. The proposal seeks to establish whether there is a sensitive period for visual influences on eye growth, and to characterize the delay in ocular growth response following visual depravation started at different ages. Spectacles lenses will be used to induce defocusing in marmosets in order to study visual regulation of refractive state. Experiments will be conducted to determine whether changes in accommodative control result from induced changes in refractive state, or whether differences in accommodative control underlie differences in visual control of eye growth. These investigations will help provide data on the origin of the widespread problem of myopia in humans.

Recent advances in animal models of experimental myopia and ocular development may offer important frameworks for the development of new and effective treatment strategies in humans. work with chicks and tree shrews has clearly established the importance of postnatal visual experience in the regulation of eye growth, contributed to our understanding of ocular mechanisms controlling refraction, and has made inroads toward understanding the biochemical mechanisms of ocular growth control. How does this work relate to humans? Research with non-human primates is the critically important link between animal experiments and human treatments. In this project, we will be examining the regulation of ocular refraction in the common marmoset. We have chosen this primate because of this small size and relatively rapid development compared to other primates. Earlier work by PI with the marmoset suggests that the growth rate of the eye is set during an early sensitive period, and visual deprivation produces axial myopia after an initial delay, even if the eye is not yet myopic when the deprivation ends. These results may have some relationship to developmental myopia in children which, once started, persists or worsens. In the proposed experiments we will examine the mechanism of early refractive change at the sensory, histological and biochemical levels. The main work on this project is being conducted at the New England College of Optometry (Boston, MA), but could no be accomplished without the assistance of the New England Regional Primate Research Center. The primate center is the principal resource for veterinarian and husbandry advice, and several experiments involving the rearing of young marmosets

DESCRIPTION (adapted from applicant's abstract): Myopia (nearsightedness) is on the rise around the world and in the United States. It affects tens of millions of Americans and, in progressive forms, is a leading cause of blindness. Earlier research with humans and experimental animal models has made it clear that the postnatal development of the eye and refractive state involves a combination of genetic and visual factors. The rise in incidence of human myopia has been associated with increases in literacy and levels of education, although the nature of the relationship is unclear. Research using animal models has established that visual stimuli related to retinal defocus regulate eye growth and refractive state. The studies described in this proposal use various visual manipulations to explore the temporal integration of visual stimuli that affect eye growth and the biochemical mechanisms that may underlie these changes. The following questions are asked: (1) How does the eye temporally integrate different visual stimuli for the regulation of eye growth? To answer this, the investigators will contrast the effects of different states of defocus or deprivation with corrected or clear vision and examine the stimulus durations necessary to elicit different ocular growth responses. (2) Do ocular circadian rhythms in IOP, axial length and choroid thickness play a role in the regulation of ocular growth? Specifically, the investigators will examine the phase relationships between these different rhythms during induced changes in ocular growth rate. (3) How do the temporal pattern and accuracy of accommodation affect the degree of blur experienced during near work tasks and when viewing through negative power spectacle lenses? These measures of accommodative behavior will then be correlated with the degree of experimental myopia induced. (4) What are the changes in scleral extracellular matrix during experimentally induced changes in ocular growth, and how are they controlled? Using ocular tissues from the other experiments, the investigators will quantify changes in scleral extracellular components and correlate them with visually induced increases and decreases in ocular growth rate. In addition, the possibility that retinoic acid synthesis by the choroids/RPE plays a role in the signal cascade from retina to sclera will be explored. This project will bring together several lines of investigation to help answer important questions relating to how myopia develops in response to altered visual experience. These studies will provide new information for understanding the association of near work, such as reading, and the development of myopia in humans.

DESCRIPTION (provided by applicant): Funds for two institutional infrastructure modules are requested to facilitate the vision research programs of 18 faculty/researchers at the New England College of Optometry. Eight of these personnel are PIs on NEI funded projects, and six others are researchers supported, in whole or part, by NEI funds. A Biostatistics Module is proposed. This module will help the College fund a formally trained biostatistician who will assist investigators on experimental design and statistical analysis of complex data sets. A Digital Imaging Module is also proposed. This will provide an experienced digital image analyst with expertise in programming, image processing, and visual stimulus control systems. This module will assist key research personnel in the development, construction, and operation of visual stimulus delivery and optical and ocular measurement systems. A major strength of the research programs at the New England College of Optometry is the multi-disciplinary approach brought to bear on issues of clinical importance. For example, experimental approaches used at the college in the study of eye growth and myopia development involve human and non-human subjects, and behavioral, clinical, and basic biological techniques. Research at the college over the past ten years has been increasingly productive and is currently funded by four R01 grants, three U10 grants, a number of U10 subcontracts, and various other sources of extramural funding. The administration strongly supports research at the college and actively plans to expand its research mission by adding seven new laboratories to the existing eleven, and also by initiating MS and PhD graduate programs in Vision Science. The modules requested in this application will greatly enhance these activities and ongoing research at the New England College of Optometry