Download here - OU Vision Research

John D. Ash, Ph.D.
Associate Professor of Ophthalmology
Adjunct Associate Professor of Cell Biology
Graduate Liaison, Oklahoma Center for Neuroscience.
Office # 405-271-3642
Fax # 405-271-3721
Email [email protected]
Web site John D. Ash, Ph.D.
Angiogenesis, Cell signaling, Developmental biology, Diabetes, Gene
expression and regulation, Mouse genetics, Neuroscience, Vision function and disease
Key Words:
Research:
In my laboratory we have three funded projects. Almost all projects involve in vivo analysis
using genetically modified mice.
Projects with associated techniques:
Project 1. The mechanism of gp130 activation in preventing retinal degeneration. We are
interested in understanding the role of the receptor gp130 in preventing neural differentiation
and in preventing neuronal cell death. Recent studies have shown that activating ligands of
gp130, including ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF) can
prevent cell death of photoreceptor neurons, caused by genetic mutations and traumatic injury.
In recent studies we have made the exciting discovery that activation of gp130 in development
reduces the expression of key transcription factors, which are necessary for the expression of
genes involved in the differentiation of neurons in the eye. We are currently using cre/lox
technology in mice to create tissue specific knockouts of gp130 to determine whether or not it is
an essential regulator of neuroprotection and neural differentiation. This project is supported by
funding from the NIH/NEI. We are also analyzing the signal transduction pathways activated
downstream of gp130 in order to identify which pathway is responsible for neuroprotection. We
are currently using conditional knockouts of STAT3, and ERK1/2, and mice that are null for Akt
isoforms.
Project 2. Regulation of pathological neovascularization by TGF-β1.
We have found that expression of transforming growth factor beta 1 (TGF-β1) prevents the
formation of stable vasculature by down regulating the expression of the Tie2 receptor in
vascular endothelial cells. We are currently studying the mechanism for Tie2 down regulation.
We have also found that TGF-β 1 blocks the recruitment of pericytes to newly formed blood
vessels during angiogenesis. These results suggest that TGF-β 1 may be a major cytokine in
the course of diabetic retinopathy by disrupting Tie2 signaling. The project is supported by
funding from American Diabetes Association.
Project 3. Identifying the role of IL6 signaling in Diabetes complications.
Inflammation is now recognized as an important mediator affecting the age of onset and severity
of diabetes and diabetic complications. Inflammatory cytokines, such as tumor necrosis factor-α,
interleukin-1β (IL-1β), IL-18, and members of the IL-6 family are elevated in diabetics. IL-6 has
been shown to be involved in the progression of both type 1 and type 2 diabetes. IL-6 levels are
elevated in the retina during diabetes. Other IL-6 family members, including ciliary neurotrophic
factor (CNTF) and Leukemia Inhibitory Factor (LIF), are expressed by glial cells and are shown
to be elevated during ischemic stress and injury. IL-6 cytokines bind and activate receptors that
require the signaling receptor gp130. Activation of gp130 leads to signal transduction through
JAK/STAT, the mitogen activated protein kinase pathway (Erk1/2), and the phosphatidylinositol
3 kinase (PI3K) and Akt pathway. By inactivating gp130 in vivo we can determine the role of IL6, and IL-6 family members in the progression and severity of diabetic complications in the
retina. This project is supported by funding from the NIH/NCRR
Recent Publications:
1. Ash, J.D., Overbeek, P.A.,. 2000. Lens-specific VEGF induces angioblast migration and
proliferation and stimulates angiogenic remodeling. Developmental Biology, 2000, 223:
383-398.
2. Ash, J.D.,. 2001. Leukemia inhibitory factor prevents photoreceptor cell death in rd-/mice by blocking functional differentiation. New insights into retinal degenerative
diseases and experimental therapy. Edited by Anderson, LaVail, and Hollyfield, Kluwer
Academic / Plenum Publishers, New York.
3. Qin C., Ash, J.D., Branton, P., Fromm, L., Overbeek, P.A., 2002, Inhibition of crystallin
expression and induction of apoptosis by lens-specific E1A expression in transgenic
mice. Oncogene, 2002, 21:1028-1037
4. Vinores, S.A., Seo, M.S., Okamoto, N., Ash, J.D., Wawrousek, E.F., Xiao, W.-H.,
Hudish, T., Drevjanik, N.L., Campochiaro, P.A., 2002, Experimental models of growth
factor-mediated angiogenesis and blood-retinal barrier breakdown. General
Pharmacology: The Vascular System 2002, 35:233-239
5. Carr DJ, Ash J, Al-Khatib K, Campbell IL., 2002, Unforeseen consequences of IL-12
expression in the eye of GFAP-IL12 transgenic mice following herpes simplex virus type
1 infection. DNA Cell Biol. 2002 May-Jun;21(5-6):467-73.
6. Jeong, J.H., Hines-Boykin, B., Ash, J.D., Dittmer, D., 2002, Tissue Specificity of the
Kaposi's Sarcoma-Associated Herpesvirus Latent Nuclear Antigen (LANA/orf73)
Promoter in Transgenic Mice. J Virol. 2002 Nov;76(21):11024-32.
7. Rajala RV, McClellan ME, Ash JD, Anderson RE., 2002, In Vivo regulation of
phosphoinositide 3-kinase in retina through light induced tyrosine phosphorylation of the
insulin receptor beta -subunit. J Biol Chem. 2002 Nov;277(45):43319-43326.
8. Rajala, RV., McClellan, ME., Ash, JD., Anderson RE., (2003). Regulation of retinal
phosphoinositide 3-kinase activity in p85alpha-subunit knockout mice. Adv. Exp. Med.
Biol. 2003, 533:369-376
9. Carr, DJ., Chodosh, J., Ash, J., and Lane, TE., (2003). Effect of Anti-CXCL10
monoclonal Antibody on Herpes Simplex Virus Type 1 Keratitis and Retinal Infection. J
Virol. 2003, 77(18):10037-46.
10. Le, Y.Z., Ash, J. D., Al-ubaidi, M., Chen, Y., Ma, J.X., Anderson, R.E., (2004) Targeted
expression of Cre recombinase to cone photoreceptors in transgenic mice. Mol Vis
2004; 10:1011-1018
11. Saban, MR., Memet, S., Jackson, DG., Ash, J., Roig, AA., Israel, A., Saban, R., (2004).
Visualization of lymphatic vessels through NF- B activity. Blood 2004, 104(10):32283230.
12. Wickham, S., Ash, J., Lane, TE., Carr, DJ., (2004) Consequences of CXCL10 and IL-6
induction by the murine IFN- 1 transgene in ocular herpes simplex virus type 1
infection. Immunologic Research 2004, 2004;30(2):191-200.
13. Huang, H., Li, F., Alvarez, RA., Ash, JD., Anderson, RE., (2004) Downregulation of ATP
synthase subunit-6, cytochrome c oxidase-III, and NADH dehydrogenase-3 by bright
cyclic light in the rat retina. Invest Ophthalmol Vis Sci. 2004, 45(8),:2489-96.
14. Sherry, D.M., Li, H., Mitchell, R., Graham, D.R., Ash, J.D. (2005), Leukemia Inhibitory
Factor (LIF) Inhibits Neuronal Development and Disrupts Synaptic Organization in the
Mouse Retina. Journal of Neuroscience Research (2005), 82:316-332
15. Graham, D.R., Overbeek, P.A., Ash, J.D., (2005), Leukemia Inhibitory Factor Blocks
expression of Crx and Nrl transcription factors to inhibit photoreceptor differentiation.
Invest Ophthalmol Vis Sci. (2005); 46 (7):2601-2610
16. Ash, J.D., McLeod, D.S., Lutty, G.A., (2005), Transgenic expression of leukemia
inhibitory factor (lif) blocks normal vascular development but not pathological
neovascularization in the eye, Mol. Vis. (2005); 11:298-308
17. Wickham, S., Lu, B., Ash, J., and Carr, DJJ., (2005) The Absence of CXCR3 Expression
Leads to an Elevation in Chemokine Expression in the Trigeminal Ganglion and Brain
Stem but Reduced Virus-Mediated Death Following Ocular Infection with Herpes
Simplex Virus Type 1, The Journal of Neuroimmunology, (2005), 162:51-59
18. Carr, D.J., Ash, J., Lane, T.E., Kuziel, W.A., Abnormal Immune Response of CCR5deficient mice to ocular infection with herpes simplex virus type 1, J Gen Virol. (2006);
87:489-499.
19. Tomasek, J.J., Haaksma, C.J., Schwartz, R.J., Voung, D.T., Zhang, S.X., Ash, J.D., Ma,
J.-X., Al-Ubaidi, M., (2006); Deletion of Smooth Muscle Alpha-Actin Alters Blood-Retina
Barrier Permeability and Retinal Function, Invest Ophthalmol Vis Sci 47(6):2693-700.
20. Haniu, H., Komori, H., Takemori, N., Singh, A., Ash, J.D., Koyama, S., Matsumoto, H.,
(2006); Proteomic Trajectory Mapping of Biological Transformtion: Application to
Developmental Mouse Retina. Proteomics. 6(11):3251-61.
21. Le, Y-Z., Zheng, L., Zheng, W., Ash, J.D., Agbaga, M-P., Zhu, M., Anderson, R.E.,
(2006); Mouse Opsin Promoter-Directed Cre Recombinase Expression in Transgenic
Mice. Molecular Vision; 12:389-98
22. Le, Y., Ash, J.D., Al-Ubaidi, M.R., Chen, Y., Ma, J., Anderson, R.E., (2006) Conditional
gene knockout system in cone photoreceptors, Adv Exp Med Biol. 2006;572:173-8.
23. Ash, J.D., Graham DR., (2006); Transgenic expression of leukemia inhibitory factor
inhibits both rod and cone gene expression. Gp130 regulates cone gene expression.
Adv Exp Med Biol. 2006;572:147-53.
24. Ueki, Y., Wang, J., Chollangi, S., Ash, J.D., (2007) STAT3 but not ERK1/2 or Akt
activation occurs during leukemia inhibitory factor induced neuroprotection of from
oxidative stress in the retina. Journal of Neuroscience. (submitted)