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Ed Levine

Assistant Professor of Ophthalmology and Visual Sciences and of Neurobiology and Anatomy

B.S. State University of New York, Albany

Ph.D. State University of New York, Stony Brook

Research

References

elevine@hmbg.utah.edu

 

Research

My lab is focused on two broad areas; (i) understanding the molecular and cellular mechanisms of retinal development, and (ii) determining the contributions of developmental mechanisms to the progression and treatment of retinal degenerative diseases.   We study the rodent retina because its developmental progression is well understood, in vitro and in vivo approaches are established, and several genetic models of retinal development and degeneration are available.   Because of these advantages, we can identify and characterize important regulatory molecules and directly assay their functions in development and degeneration.

(i) Molecular and Cellular Mechanisms of Retinal Growth during Development Retinal growth critically depends on the expansion of the stem cell and progenitor cell populations through cell proliferation. Too little proliferation can result in birth defects such as microphthalmia; too much can result in hyperplasia or retinoblastoma.   Little is known about the regulation of proliferation, though such knowledge could provide the foundations for strategies to treat ocular birth defects; for stem cell therapies of retinal degenerations; to prevent pathological growth associated with diseases such as retinoblastoma and diabetic retinopathy.

Currently, we are investigating the function of the homeobox gene Chx10 in retinal progenitor cell proliferation. Mutations in the Chx10 gene cause microphthalmia in humans and mice, primarily through a profound reduction in retinal progenitor cell proliferation.   We found that genetic elimination of p27 Kip1 , a negative regulator of the cell cycle, significantly alleviates the microphthalmia birth defect caused by the Chx10 mutation. This, with other observations, establishes a definitive link between Chx10, cell cycle regulation, and proliferation.   The interaction between Chx10 and p27 Kip1 is not simple, however, and emerging data suggests multiple roles for Chx10 in regulating proliferation.   Thus, we are determining the levels of proliferation control regulated by Chx10, identifying the requirements for Chx10 in the signal transduction pathways of growth factors, and characterizing direct downstream transcriptional targets.   Our primary approaches involve genetics, genomics, proteomics, and cell culture.

(ii) Developmental Mechanisms, s tem c ells, and Retinal Degenerations In inherited retinal degeneration, the primary genetic lesion typically occurs in one cell type such as photoreceptors. However, other retinal cell types such as glia are also affected by becoming reactive, an injury response that is probably mediated by signaling from degenerating photoreceptors.   We are studying the relationship between glial reactivity and photoreceptor degeneration for the following reasons.   First, we want to know whether the glial response contributes to the progression of the degeneration.   Second, the signals from the dying photoreceptors to the Muller glia may be good targets for developing strategies to delay, and ultimately prevent degeneration.   We are currently developing transgenic mice that will allow us to employ genomics based techniques to discover important genes that function in the photoreceptor-glial interaction in healthy and degenerating retinas.

Recent studies suggest that glia can de-differentiate into stem cells and produce neurons in the brain.   Since the retinal glia derives from the same progenitor cells as retinal neurons, they may have the genetic instructions in place for making photoreceptors and other retinal cell types.   Our goal is to define the genetic and environmental conditions that are permissive for neuronal production from Muller glia with the ultimate goal of replacing degenerating photoreceptors in the human retina.

References