Overall Mission: understanding the mechanisms of retinopathy and vision impairment in response to trauma or metabolic insults (obesity & diabetes) in the hope of identifying effective therapeutics to prevent blindness.
During the past two-decades, my research has focused on studying the role of oxidative stress and inflammation in cardiovascular complications of diabetes. As a Pharmacist and Vascular Biologist, my work contributed significantly to understanding how diabetes-generated free radicals adversely affect retina vasculature as well as coronary artery and aortic endothelial cells. This work was funded by a number of intramural and extramural grants that were funded to myself (multi-year grants from AHA, JDRF and NEI) as well as my trainees three AHA pre-doctoral fellowships (2010-2012), (2012-2014) and (2015-2016) and an AHA post-doctoral fellowship (2013-2014). (see details under my entire career).
As a junior faculty member, I developed a genuine interest in peroxynitrite as a signaling molecule capable of modifying proteins and altering vascular function via posttranslational protein modification. Our work was the first to show that tyrosine nitration as a molecular switch between survival and death in endothelial cells (nitration of PI-3kinase), neuronal cells (nitration of TrkA, NGF receptor) and Muller cells (nitration of glutamine synthetase), See list. Our work also demonstrated a nitration-independent effect of peroxynitrite modulating redox state of cells via S-glutathionylation, See list.
After establishing the Retinopathy Lab in 2006, I took a new challenge of studying the role of nerve growth factor (NGF) in the diabetic retina. My group has made the discovery that diabetes-induced peroxynitrite impairs the proteolytic cleavage and maturation of the NGF precursor (proNGF) to its mature form (NGF). Over the past decade, our work unraveled and established the impact of proNGF and its receptor p75NTR. Our work identified also that diabetes not only impairs NGF but the activation of its receptor TrkA, See list
Patent # 62/819,183: Promise to rescue vision in diabetic patients.
We made the discovery also that treatments that target proNGF/p75NTR pathway could better harness the endogenous NGF/TrkA signal resulting in better out come. This concept was validated using p75NTR knockout mice and our pioneering transgenic models that overexpress cleavage-resistant proNGF. The next step was to identify a viable pharmacological tool to target p75NTR in diabetes. Our collaborative efforts with Dr. Frank Longo
, Chair, Dept. of Neurology Stanford University using a novel and the first orally bioavailable p75NTR modulator (LM11A-31)
developed by his group. Our recent publication
entitled “Modulation of the p75 neurotrophin receptor using LM11A-31 prevents diabetes-induced retinal vascular permeability in mice via inhibition of inflammation and the RhoA kinase pathway” was published after Patent# 62/819,183 filed by the VA on behalf of the authors.
TXNIP between reductive stress and ER stress.
Our studies using acute neurotoxicity models identified thioredoxin interacting protein (TXNIP) as a pro-oxidative, pro-apoptotic and pro-inflammatory protein in the retina. While researchers including myself focused on oxidative stress, our work on TXNIP knockout mice lead to the discovery of a new concept of "reductive stress". This concept was validated in both in vivo and in vitro studies where deletion of TXNIP resulted in acute shift of the redox balance toward diminished free radicals and accumulation of reduced-glutathion. Interestingly, shifting the homeostasis to reductive stress inhibited VEGF angiogenic and survival signal. These studies were published
in Antioxidants and Redox Signal and was made the cover of the December issue.
The other unique area of work is the interplay between TXNIP as a mediator of inflammation in response to high fat diet (HFD) and how HFD induces and regulate TXNIP expression. Our work was the first to show that TXNIP is required for TXNIP-inflammasome activation in the retina leading to vascular degeneration. This hypothesis was validated also in other organs including liver and critical limb ischemia. Further, our recent work showed for the first time a two-way regulation mechanism by which ER-stress mediators stabilize and sustain TXNIP expression. In return, TXNIP expression is required to sustain ER-stress mediators in response to hypoxia or ischemia. See List of publication.
Google Scholar: https://scholar.google.com/citations?hl=en&user=nDwQ5q8AAAAJ&view_op=list_works