The overall goal of this proposal is to provide the principal investigator (PI) with the experience and skills necessary to become an independent researcher studying basic mechanisms of retinal neovascular disease. The scientific focus of this proposal is to gain a better understanding of pathological angiogenesis in the eye, a principal cause of irreversible blindness worldwide. Emerging evidence suggests a shared etiology for neovascularization in the eye in which local hypoxia leads to upregulation of the hypoxia inducible factor (HIFs). HIFs are a family of transcription factors which stimulate production of several """"""""hypoxia inducible"""""""" genes, including angiogenic growth factors (e.g. vascular endothelial growth factor or VEGF), which, in turn, promote the growth of (leaky) blood vessels. Of interest, significant progress in our understanding of the regulation of HIFs in pathological angiogenesis has come from recent work examining the dysregulation of HIFs in patients with von Hippel-Lindau (VHL) disease. Retinal hemangioblastomas are neovascular tumors that remain the most common clinical manifestation in patients with VHL disease, often manifesting with profuse edema and resulting in profound loss of vision. The VHL protein (pVHL) targets HIFs for degradation. Therefore, loss of pVHL in patients with VHL disease results in dysregulation of HIFs and over expression of hypoxia-inducible genes, mimicking pathological angiogenesis. The underlying hypothesis of this proposal is that VHL retinal hemangioblastomas are a model for pathological angiogenesis and provide an ideal genetic model to examine the role(s) of HIFs and their targets in the breakdown of the inner blood- retinal barrier (iBRB), a poorly understood, but critical early event in retinal neovascular disease. To address this hypothesis, three specific aims are proposed:
Aim 1 : To examine the necessity for HIFs in the breakdown of the iBRB.
Aim 2 : To determine if HIF dysregulation is sufficient to promote breakdown of the iBRB.
Aim 3 : To determine the relative contribution of HIF-dependent growth factors in breakdown of the iBRB. In the course of the proposed research and selected didactic activities, the PI will gain invaluable training experience and mentoring in studying the molecular pathogenesis of retinal neovascular disease. This expertise is deemed essential for the PI who aspires to develop an independent research program studying basic mechanisms of retinal pathological angiogenesis.

Public Health Relevance

Retinal neovascular disease is the leading cause of irreversible blindness in the developed world. This proposal intends to study the underlying cellular and biochemical changes leading to the breakdown of the inner blood-retinal barrier by studying a novel genetic model for retinal neovascular disease. In addition to numerous retinal diseases (e.g. proliferative diabetic retinopathy, ischemic vascular occlusions, retinopathy of prematurity, and macular degeneration), these studies may promote a greater appreciation for the cause of other ocular diseases which involve dysregulated angiogenesis (e.g. ocular tumors and neovascular glaucoma).

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08EY021189-04
Application #
8650284
Study Section
Special Emphasis Panel (ZEY1-VSN (02))
Program Officer
Agarwal, Neeraj
Project Start
2011-06-01
Project End
2016-03-31
Budget Start
2014-06-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$179,577
Indirect Cost
$13,302
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rodrigues, Murilo; Kashiwabuchi, Fabiana; Deshpande, Monika et al. (2016) Expression Pattern of HIF-1α and VEGF Supports Circumferential Application of Scatter Laser for Proliferative Sickle Retinopathy. Invest Ophthalmol Vis Sci 57:6739-6746
Hu, Ke; Babapoor-Farrokhran, Savalan; Rodrigues, Murilo et al. (2016) Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma. Oncotarget 7:7816-28
Babapoor-Farrokhran, Savalan; Jee, Kathleen; Puchner, Brooks et al. (2015) Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci U S A 112:E3030-9
Sodhi, Akrit; Montaner, Silvia (2015) Angiopoietin-like 4 as an Emerging Therapeutic Target for Diabetic Eye Disease. JAMA Ophthalmol 133:1375-6
Feng, Xiaodong; Degese, Maria Sol; Iglesias-Bartolome, Ramiro et al. (2014) Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 25:831-45
Asnaghi, Laura; Lin, Michael H; Lim, Kah Suan et al. (2014) Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation. PLoS One 9:e105372
Whitcup, Scott M; Sodhi, Akrit; Atkinson, John P et al. (2013) The role of the immune response in age-related macular degeneration. Int J Inflam 2013:348092
Rodrigues, Murilo; Iliff, Nicholas T; Eberhart, Charles G et al. (2013) Scleral penetration of an unusually aggressive case of a retinal hemangioblastoma. Can J Ophthalmol 48:e67-71
Sophie, Raafay; Hafiz, Gulnar; Scott, Adrienne W et al. (2013) Long-term outcomes in ranibizumab-treated patients with retinal vein occlusion; the role of progression of retinal nonperfusion. Am J Ophthalmol 156:693-705
Hsu, Annie W; Sodhi, Akrit; Eberhart, Charles et al. (2013) Regression of choroidal neovascularization in response to systemic chemotherapy for cancer. Can J Ophthalmol 48:e80-2

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