The Role of Endoplasmic Reticulum Stress in Diabetes Associated Impaired Angiogenesis
Grant
Overview
abstract
The high morbidity and mortality associated with diabetes-related cardiovascular disease (CVD) are major medical challenges and notably in Qatar where a high percentage is affected by diabetes. Epidemiological studies reveal that 2 out of 3 individuals with diabetes die from ischemic heart disease or stroke and those who survive face a more challenging prognosis than non-diabetic subjects. The unfavourable prognosis among diabetic individuals who develop CVDs has been correlated to oxidative stress ensuing endothelial dysfunction and subsequent impairment of angiogenesis. The Endoplasmic Reticulum (ER) stress response, otherwise known as the Unfolded Protein Response (UPR), has been implicated in hyperglycemia-associated endothelial dysfunction, however, its role in the impairment of angiogenesis in diabetes remains unclear. In view of the increased functional severity of CVD in diabetic subjects and the likely contribution of hyperglycemia-associated ER stress–mediated endothelial dysfunction, we hypothesize that hyperglycemia/diabetes-mediated protein unfolding/misfolding in the ER and the related UPR in endothelial cells could play a vital role in the impairment of angiogenesis, the reversal of which should prove valuable for the prophylaxis of CVDs in diabetic subjects. Investigations on the molecular mechanisms of impairment of angiogenesis in diabetes and possible therapeutic strategies with special reference to ER stress form the basis for this proposal. The project aims to prioritize research in PI's area of interest as a part of career development & service to humanity. Studies report that 16.7% of the adult Qatari population is affected by diabetes with an increasing burden of related cardiovascular diseases (CVDs), highlighting the need for prioritizing research in this area. The project aims to establish a strong research culture & build research capacity that not only raises Qatar’s profile within the international community, but also benefits world health. The pathological vascular repair/remodeling & aberrant angiogenesis is one of the prime underlying causes of a higher incidence of CVD complications in diabetic subjects, which is a major medical challenge owing to high rates of morbidity & mortality. In a diabetic milieu the conventional surgical revascularization interventions such as bypass surgery & angioplasty tend to have a higher failure rate, leaving many diabetic subjects burdened by CVDs with no option for treatment. The current proposal aims to advance our understanding of the pathophysiology of diabetes associated impaired angiogenesis, related CVDs, facilitate the discovery of new treatment regimens for CVDs whereby the molecular mechanisms involved may be reversed to induce angiogenesis (therapeutic angiogenesis) & mitigate disease progression, ultimately improving quality of life in affected individuals.
