Debra A. Thompson, Ph.D.

Professor, Biological Chemistry

B.S., Western Michigan University
Ph.D., Michigan State University
Postdoctoral, Massachusetts Institute of Technology

Research Profile

The light-absorbing rod and cone photoreceptor cells of the retina are highly specialized structures that are easily damaged by trauma, disease, aging, and genetic mutations, resulting in a number of blinding conditions. The retinal pigment epithelium (RPE) is an adjacent monolayer of polarized cells that provides critical support for the normal function and viability of the photoreceptors. Leber congenital amaurosis (LCA) is a devastating inherited condition that results in photoreceptor cell death and profound visual disability in children and young adults. LCA is at the center of current efforts to develop targeted therapies for inherited retinal disease and degeneration, with Phase I clinical trials currently underway. Thus, elucidating the function and functional context of known LCA genes, as well as the associated pathogenetic mechanisms, is a critical area of study relevant to current efforts in translational vision research.

Work in our laboratory contributed to the identification of RPE65, LRAT, and RDH12 as LCA genes, as well as MERTK mutations in juvenile retinitis pigmentosa. RPE65 (retinoid isomerohydrolase 1) and LRAT (lecithin retinol acyl transferase) have established roles in the visual cycle reactions occurring in the RPE and necessary for the conversion of vitamin A to 11-cis retinal, the chromophore of the rod and cone visual pigments. RDH12 (retinol dehydrogenase 12) is a member of the conserved family of short chain dehydrogenases/reductases, a number of which are expressed in retina and are required for visual cycle function. In contrast, MERTK encodes mer receptor tyrosine kinase that is necessary for phagocytic clearance of photoreceptor outer segment (OS) membranes that are shed in diurnal rhythm into the subretinal space and taken up by the RPE.

A major focus of our current research is on molecular characterization of the visual cycle mechanism that provides a constant supply of 11-cis retinal required for light-induced signal transduction, for stability and trafficking of visual pigment proteins, and for photoreceptor cell viability. In one set of studies, we are working to define the role of the disease gene RDH12 within the network of RDH isoforms present in the photoreceptor cells. RDH enzymes are needed to reduce all-trans retinal released from bleached visual pigments to all-trans retinol that can be efficiently removed from the photoreceptor cells. We are evaluating mouse models of RDH-deficiency in terms of similarities and differences with the human disease phenotype to further define the mechanism of detoxification of all-trans retinal and recycling of vitamin A in the visual response.

Our second focus is on the mechanism of RPE phagocytosis, in which MERTK signaling plays an essential role. MERTK is widely expressed in various tissues in which it contributes to the clearance of apoptotic cells, tissue homeostasis, the immune response, and innate immunity. MERTK signaling is proposed to involve cross-talk with alphavbeta5 integrin receptors, as well as activation of small G proteins involved in mobilizing actin reorganization. We are working to delineate the protein interactions and signaling events occurring downstream of MERTK and necessary for RPE phagocytic uptake of OS, in studies that build on the prediction that remodeling of the RPE cytoskeleton involves mechanisms conserved, in part, with those occurring in cells of the immune system.

Awards

1995 Career Development Fund for Women Faculty Award, University of Michigan
1995 Rackham Partnership Program Award, Sponsor, University of Michigan
1999 Lew R. Wasserman Merit Award, Research to Prevent Blindness
2005 Elizabeth Caroline Crosby Research Award, NSF ADVANCE Project
2008 Senior Scientific Investigator Award, Research to Prevent Blindness

PubMed Search Term : thompson da

Selected Publications

Janecke, A.R., Thompson, D.A., Utermann, G., Becker, C., Hübner, C.A., Schmid, E., McHenry, C.L., Nair, A.R., Rüschendorf, F., Heckenlively, J.R, Wissinger, B., Nürnberg, P., and Gal, A. Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset retinal dystrophy. Nature Genet. 36, 850-854, 2004.

Hemati, N., Feathers, K.L., Chrispell, J.D., Reed, D.M., Carlson, T.J., Thompson, D.A. RPE65 surface epitopes, protein interactions, and expression in rod- and cone-dominant species. Mol. Vis. 11, 1151-65, 2005. http://www.molvis.org/molvis/v11/a133/v11a133-hemati.pdf

Thompson, D.A., Janecke, A.R., Lange, J., Feathers, K.L., Hubner, C.A., McHenry, C.L., Stockton, D.W., Rammesmayer, G., Lupski, J.R., Antinolo, G., Ayuso, C., Baiget, M., Gouras, P., Heckenlively, J.R., den Hollander, A., Jacobson, S.G., Lewis, R.A., Sieving, P.A., Wissinger, B., Yzer, S., Zrenner, E., Utermann, G., Gal, A. Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. Hum. Mol. Genet. 14, 3865-75, 2005. http://hmg.oxfordjournals.org/cgi/reprint/14/24/3865

Jacobson, S.G., Cideciyan A.V., Aleman T.S., Sumaroka A., Schwartz S.B., Windsor E.A.M., Roman A.J., Heon E., Stone E.M., and Thompson D.A. RDH12 and RPE65, visual cycle genes causing Leber congenital amaurosis, do not share disease mechanism and should not share therapeutic strategy. Invest. Ophthalmol. Vis. Sci. 48, 332-338, 2007.

Kurth, I., Thompson, D.A.*, Rüther, K., Feathers, K.L., Chrispell, J.D., Schroth, J., McHenry, C.L., Schweizer, M., Gal, A., and Hübner, C.* (*co-corresponding authors) Targeted disruption of the murine retinal dehydrogenase gene Rdh12 does not limit visual cycle function. Mol. Cell. Biol. 27, 1370-1379, 2007. http://mcb.asm.org/cgi/reprint/27/4/1370

Schuster, A., Janecke, A.R., Wilke, R., Schmid, E., Thompson, D.A., Utermann, G., Wissinger, B., Zrenner, E., and Gal, A. The Phenotype of Early-Onset Retinal Degeneration in Persons with RDH12 Mutations. Invest. Ophthalmol. Vis. Sci. 48, 1824-1831, 2007.

Feathers, K.L., Lyubarsky, A.L., Khan, N.W., Teofilo, K., Swaroop, A., Williams, D,S., Pugh, E.N. Jr., and Thompson, D.A. Nrl-knockout mice deficient in RPE65 fail to synthesize 11-cis retinal and cone outer segments. Invest. Ophthalmol. Vis. Sci. 49, 1126-1135, 2008. http://www.iovs.org/cgi/reprint/49/3/1126

Huang, X., Finerty, P. Jr., Walker, J.R., Butler-Cole, C., Vedadi, M., Schapira, M., Parker, S.A., Turk, B.E., Thompson, D.A., Dhe-Paganon, S. Structural insights into the inhibited states of the Mer receptor tyrosine kinase. J. Struct. Biol. 2008 Nov 5. [Epub ahead of print] http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WM5-4TVHSN5-1-K&_cdi=6925&_user=99318&_orig=search&_coverDate=11%2F05%2F2008&_sk=999999999&view=c&wchp=dGLbVlz-zSkzS&md5=644521cfd3be02f90fcda8a8b2cd7e30&ie=/sdarticle.pdf