Khadija Rafiq, PhD
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Cardiovascular disease, including heart failure, is the primary cause of death in patients with diabetes. A contributing factor to heart failure in such patients is the development of diabetic cardiomyopathy. Several advances in the treatment of patients with diabetic cardiomyopathy have improved survival. However, this disease process is still pre-eminent in affecting the morbidity and mortality of patients with diabetes. Understanding the mechanisms that lead to diabetes will lead to developing a novel therapeutic target to treat patients with diabetic cardiomyopathy.
Dr. Khadija Rafiq’s Laboratory has had extensive experience in identifying the cellular and molecular mechanisms involved in immune system responses to stress or injury. Dr. Rafiq started her career studying the mechanisms regulating cytokine production in leukocytes. The goals of these studies were to identify novel signaling mechanisms that control autoimmune disease and tumor prevention. Over the past several years she has been investigating how the immune system affects cardiac myocyte growth and cardiac function with particular focus on signaling molecules that are activated by inflammatory proteases. She has been able to demonstrate that neutrophil-derived proteases induced cardiac myocyte anoikis (a form of apoptosis induced by loss of cell substrate).
As a faculty member, Dr. Rafiq plans to study the molecular and cellular mechanisms leading to diabetic cardiomyopathy with a focus on the role of inflammatory proteases. Her hypothesis is that disruption in inflammation might be linked to diminished insulin responsiveness and to maladaptive cardiac structural and functional consequences observed in diabetes. Although several studies showed the role of cytokines and oxygen free radicals in developing diabetic cardiomyopathy, almost nothing is known about the role of inflammatory serine proteases in the development of this disease. In addition, the role of inflammation is still controversial, as both positive and negative effects of inflammation have been observed. Using intact tissue and cell culture models, Dr. Rafiq’s research interest is focused on elucidating the mechanisms by which inflammatory proteases induce myocyte death and subsequent cardiac remodeling.
Our group has recently found the implication of inflammatory proteases in the development of diabetic cardiomyopathy. Using mice deficient in major inflammatory serine proteases, we found that inflammatory proteases play an important role in the development of several symptoms associated with diabetes without affecting blood glucose levels. We are currently investigating the relevance of these findings on other models of diabetic cardiomyopathy using a unique set of reagents and transgenic mice. Our laboratory routinely investigates the mechanistic role of novel signaling molecules in-vitro and then translates these findings to animal models of heart failure to prove that the process we are studying has relevance to human cardiac disease.
Our long term goal is to develop, implement, and disseminate interventions for reducing the burden of obesity and diabetes in low-income communities. As inflammation is associated with both type 1 and type 2 diabetes, developing anti-inflammatory approaches may stand as promising immunotherapeutic strategy. Further research would focus on inducing immune tolerance and applying the therapeutic agents to inhibit ongoing pathogenic cell responses and reverse established pathology.
Dr. Rafiq's laboratory studies the molecular and cellular mechanisms involved in myocardial cell death. Inflammatory cells and their proteases are considered a key element that orchestrate myocardial repair. Although beneficial at early stages, inflammatory proteases may contribute to myocyte death and subsequent alterations in both the geometry and mechanical properties of the heart. Using intact tissue and cell culture models, Dr. Rafiq’s research interest focuses on elucidating the role of inflammatory serine proteases in the development of diabetic cardiomyopathy. It is well known that inflammation plays a role in developingf diabetic cardiomyopathy. However, in all these studies the action of inflammatory pathways has focused on action of oxidative stress or cytokines/chemokines and their role in myocyte growth and extracellular matrix remodeling during the development of diabetic cardiomyopathy. Dr. Rafiq’s laboratory suggests a novel mechanism for entry into pathways that modulate IR/IGF-1R signaling and myocyte dysfunction by inflammatory serine proteases. IR/IGF-1R signaling is anticipated to assume importance in maintaining myocyte metabolism and survival and in increasing myocardial protection in response to ischemia or ischemia reperfusion injury. Current therapies with insulin or IGF-1 administration have been shown to restore IR/IGF-1R signaling and to offer cardio-protection. However, excessive or inappropriate use of these therapies has been shown to increase the risk of cardiovascular diseases in diabetic patients. Therefore, our lab tests the effectiveness of inflammatory serine proteases blockade therapy in preventing/attenuating IR/IGF-1R signaling downregulation and protecting the myocardium during the development of diabetic cardiomyopathy.