Diabetic retinopathy (DR), the leading cause of blindness in working age adults in the US, is characterized by neurodegeneration, glial reactivity, inflammation and acellular capillary formation that eventually lead to retinal neovascularization and blindness. Given the limited and invasive treatments available only for advanced stages of DR, there is a great need to identify novel molecular targets for earlier therapeutic intervention. Our long-term goal is to identify such targets for DR by probing the relationships between glial inflammation and vascular injury. For this proposal, our objective is to understand how disruption of nerve growth factor (NGF) homeostasis in diabetes can lead to accumulation of its precursor proNGF and upregulation of the death receptor p75NTR, leading to vascular injury. The central hypothesis is that the diabetes-upregulated proNGF/p75NTR axis causes acellular capillary formation via direct activation of the apoptotic JNK pathway in endothelial cells (EC) that is sustained by paracrine release of proNGF in Muller cells. This hypothesis is supported by our published work and our new preliminary findings showing that stress-induced proNGF/p75NTR expression in the retina is associated with glial reactivity, release of inflammatory mediators and marked acellular capillary formation. These effects were mitigated by knocking down or deleting p75NTR expression. Furthermore, studies using high glucose (HG)-maintained retinal cultures show that proNGF stimulates its own expression in Muller cells but not in EC. In turn, proNGF can directly activate the p75NTR/JNK apoptotic pathway in EC. Now we are uniquely poised to quantify these relationships more precisely using newly developed animal models in conjunction with cell culture studies. To test our central hypothesis and understand the role of p75NTR in glial-vascular interactions in DR, the following Aims are proposed:
Aim1. Test the hypothesis that diabetes-induced proNGF/p75NTR causes retinal acellular capillaries.
Aim2. Test the hypothesis that cleavage of p75NTR to release ICD is essential to activate JNK in EC.
Aim3. Test the hypothesis that p75NTR is required for sustained release of proNGF and vascular injury. We believe that completing the proposed studies will identify several therapeutic targets that could be clinically translated to diabetic patients and prevent the progression of DR.
We propose a combined approach of using knockout mice that lack the neurotrophin receptor p75NTR in vasculature as well as isolated retinal glial and vascular cells to unravel the unexplored role of proNGF as a novel mediator of diabetic retinopathy. This research will identify several potential therapeutic targets that can be translated to clinical studies. This will give diabetic patients an opportunity to supplement their blood glucose control with additional therapies to prevent vision loss in diabetic retinopathy.
|Shanab, Ahmed Y; Elshaer, Sally L; El-Azab, Mona F et al. (2015) Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1). Angiogenesis 18:137-50|
|Soliman, Sahar; Ishrat, Tauheed; Pillai, Anilkumar et al. (2014) Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B. J Pharmacol Exp Ther 349:444-57|
|Mohamed, Islam N; Hafez, Sherif S; Fairaq, Arwa et al. (2014) Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia 57:413-23|
|Abdelsaid, Mohammed A; Matragoon, Suraporn; Ergul, Adviye et al. (2014) Deletion of thioredoxin interacting protein (TXNIP) augments hyperoxia-induced vaso-obliteration in a mouse model of oxygen induced-retinopathy. PLoS One 9:e110388|
|Mysona, Barbara A; Shanab, Ahmed Y; Elshaer, Sally L et al. (2014) Nerve growth factor in diabetic retinopathy: beyond neurons. Expert Rev Ophthalmol 9:99-107|
|Rozette, Nicole A; Matragoon, Suraporn; Sethi, Shivani et al. (2014) Systemic effects of ophthalmic cyclopentolate on body weight in neonatal mice. Neonatology 106:37-41|
|El-Azab, M F; Baldowski, B R B; Mysona, B A et al. (2014) Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury. Br J Pharmacol 171:1299-313|
|Puttabyatappa, Yashoda; Stallone, John N; Ergul, Adviye et al. (2013) Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels. J Pharmacol Exp Ther 345:7-14|
|Mysona, Barbara A; Al-Gayyar, Mohammed M H; Matragoon, Suraporn et al. (2013) Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. Diabetologia 56:2329-39|
|El-Kenawi, Asmaa E; El-Remessy, Azza B (2013) Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales. Br J Pharmacol 170:712-29|
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