|
| Ching-Kang Jason
Chen, Ph.D.
|
| Goal: To understand the mechanisms of vertebrate
phototransduction and light-dependent photoreceptor degeneration
|
|
|
|
|
The
dying mouse photoreceptor cells in a retina from the rhodopsin kinase
knockout (RK-/-) mice after 24-hour light exposure as visualized by
fluorescent dUTP labeling of the degraded genomic DNA fragments.
1. Genetic dissection of the rod and cone phototransduction pathways.
Gene targeting technologies are instrumental to understanding many
biological systems. We are
currently producing transgenic mice in which the integrities and the
dosages of rhodopsin kinase (RK), GRK7, RGS9, phosducin and Gb5
are altered. These mice will
allow us to determine the key steps that shape the response kinetics of
rod and cone photoreceptors to light.
|
2.
Characterization of the light-dependent photo-receptor degeneration in RK-/-,
RGS9-/-, Gb5-/- and
Arrestin-/- mice. Defects
in recovery of photo-transduction lead to light-dependent photoreceptor
death (see picture above). We
are developing genetic, biochemical, and molecular biological means to
find the mechanism of this cell death process.
Understand-ing this light-dependent degenerative pathway can help
explain the progression of photoreceptor loss seen in age-related macular
degeneration, retinitis pigmentosa and many other retinal diseases.
3. Biochemical characterization of the seventh member of the
G-protein coupled receptor kinase family (GRK7).
We have isolated GRK7, a potential cone opsin kinase, from bovine
and human retinas. We are
producing functional GRK7 in various expression systems and comparing it
with RK on substrate specificity, affinity for recoverin, and roles of
post-translational modifications. The
intrinsic difference between GRK7 and RK may be an integral part of the
difference in light responses between rod and cone photoreceptors. |
| Ongoing
Collaborations |
|
M.E.
Burns, University of California, Davis -
Single rod recording
E.N.
Pugh, University of Pennsylvania - ERG
J.
Frederick, University of Utah - Electron microscopy
W
Baehr, University of Utah - GRK7 characterization
B. Williardson, Brigham Young University,
Utah - Phosducin knockout mice
M.I.
Simon, California Polytechnic - Retinal DNA microarrays and Gb5
knockout mice
J.
Schwartz, California Polytechnic - Striatal dopamine signaling
of RGS9-/- mice
|
| More
Information: |
| Ching-Kang
Jason Chen, Ph.D. |
| Department
of Ophthalmology and Visual Sciences, Moran Eye Center |
| University
of Utah Health Sciences Center |
| 15
North 2030 East, Room 3110 |
| Salt
Lake City, UT 84112-5330 |
| Phone:
801.585.5258 |
| Fax:
801.585.3501 |
| Email: jason@hmbg.utah.edu |
|
|
| Selected
Publications |
| Chen
C-K, Inglese J, Lefkowitz R, Hurley JB (1995). Ca2+-dependent
interaction of recoverin with rhodopsin kinase. J Biol Chem 270: 18060
Chen
C-K, Wieland T, Simon MI (1996). RGSr, a retinal specific
RGS protein, binds an intermediate conformation of transducin and
enhances recycling. Proc
Natl Acad Sci USA 93: 12885
Chen C-K, Burns ME,
Spencer M, Niemi G, Chen J, Hurley JB, Baylor DA, Simon MI (1999).
Abnormal photo-responses and light-induced apoptosis in rods lacking
rhodopsin kinase. Proc
Natl Acad Sci USA 96: 3718
Chen C-K, Burns ME, He
W, Wensel TG, Baylor DA, Simon MI (2000). Slowed recovery of rod
photoresponse in mice lacking the GTPase accelerating protein
RGS9-1. Nature
403: 557
Lyubarsky AL, Chen
C-K, Simon MI, Pugh EN (2000). Mice lacking G-protein
receptor kinase 1 (GRK1) have profoundly slowed dark adaptation of
cone-driven retinal responses.
J Neurosci 20: 2209
Kovoor, A, Chen C-K,
He W, Wensel TG, Simon MI, Lester H (2000). Co-expression of Gb5
enhances the function of two GGL domain-containing RGS proteins.
J Biol Chem 275: 3397
Lyubarsky
AL, Chen C-K, Naarendorp F, Zhang X, Wensel T, Simon MI, Pugh
EN (2001). RGS9-1 is required for normal inactivation of mouse cone
phototransduction. Submitted
|
|
|
|
|
|
|
|
|
|
|
|
