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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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University of Georgia
Schools of Pharmacy
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Elshaer, Sally L; El-Remessy, Azza B (2018) Deletion of p75NTR prevents vaso-obliteration and retinal neovascularization via activation of Trk- A receptor in ischemic retinopathy model. Sci Rep 8:12490
Mohamed, Riyaz; Coucha, Maha; Elshaer, Sally L et al. (2018) Inducible overexpression of endothelial proNGF as a mouse model to study microvascular dysfunction. Biochim Biophys Acta Mol Basis Dis 1864:746-757
Elshaer, Sally L; Mohamed, Islam N; Coucha, Maha et al. (2017) Deletion of TXNIP Mitigates High-Fat Diet-Impaired Angiogenesis and Prevents Inflammation in a Mouse Model of Critical Limb Ischemia. Antioxidants (Basel) 6:
Elshaer, Sally L; El-Remessy, Azza B (2017) Implication of the neurotrophin receptor p75NTR in vascular diseases: beyond the eye. Expert Rev Ophthalmol 12:149-158
Mohamed, Riyaz; Shanab, Ahmed Y; El Remessy, Azza B (2017) Deletion of the Neurotrophin Receptor p75NTR Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model. J Diabetes Metab Disord Control 4:
Elshaer, Sally L; Lorys, Renee E; El-Remessy, A B (2016) Cell Therapy and Critical Limb Ischemia: Evidence and Window of Opportunity in Obesity. Obes Control Ther 3:
Fouda, Abdelrahman Y; Artham, Sandeep; El-Remessy, Azza B et al. (2016) Renin-angiotensin system as a potential therapeutic target in stroke and retinopathy: experimental and clinical evidence. Clin Sci (Lond) 130:221-38
Ishrat, Tauheed; Mohamed, Islam N; Pillai, Bindu et al. (2015) Thioredoxin-interacting protein: a novel target for neuroprotection in experimental thromboembolic stroke in mice. Mol Neurobiol 51:766-78
Mysona, B A; Matragoon, S; Stephens, M et al. (2015) Imbalance of the nerve growth factor and its precursor as a potential biomarker for diabetic retinopathy. Biomed Res Int 2015:571456
Shanab, Ahmed Y; Mysona, Barbara A; Matragoon, Suraporn et al. (2015) Silencing p75(NTR) prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina. Mol Ther Methods Clin Dev 2:15013

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