The focus of Dr. Cullen’s research is to determine how alcohol or its metabolite, acetaldehyde, affect the development of atherosclerosis and alter the immune response. While studies have demonstrated abnormal adaptive and innate immunity and an increased risk of heart attack as a result of alcohol intoxication or abuse, the precise cellular mechanisms whereby alcohol elicits these effects are unclear.
Alcohol and Atherosclerosis: The investigation of the effects of ‘moderate' and 'binge' alcohol consumption and it’s metabolite, acetaldehyde, on inflammation and vascular remodeling, pivotal in the development and destabilization of the atherosclerotic plaque, are underway. These studies utilize the genetically modified apolipoprotein E knockout (apo E k/o) mice, which after surgical intervention and a high fat diet, develops an unstable atherosclerotic plaque with many of the key characteristics seen in humans. The pathology of many diseases is based on the increased expression of certain genes, and our lab employs a novel technique of localized perivascular in vivo gene knockdown in order to identify these genes.
Alcohol and the Immune Response: Using a humanized mouse that is engrafted with human hematopoietic stem cells to generate a functional human immune system we are determining how alcohol or it’s metabolite, acetaldehyde, alter the expression of human monocyte inflammatory mediators and receptors and alter the immune system. This research should provide valuable new information central to our understanding of the effects of alcohol intoxication or abuse on the development of complications in patients after surgery, infection or trauma. Because mortality from surgical, infectious or trauma-related complications is so high following alcohol intoxication or abuse, understanding precisely how alcohol increases this risk is clearly of major significance and clinical importance, and will provide significant new information that should enable the development of potential targets for therapeutic modulation which would enhance tissue repair and restoration.
Dr. Morrow’s research has a central focus on developmental signaling pathways such as Notch and Hedgehog (Hh) which play a pivotal role in cell fate determination in adult Vascular Cells. Vascular smooth muscle cell growth plays a prominent role in neointimal formation during the pathogenesis of atherosclerosis, hypertension and vascular remodeling in response to injury. However, how vascular smooth muscle cell growth is regulated remains poorly understood. Using novel in vitro technologies (perfused transcapillary) in conjunction with an established model of flow- induced vascular remodeling (carotid ligation model) and novel technologies such as laser capture microscopy and in- vivo siRNA delivery, the goal of our research is to delineate the role of a Hh/VEGF/Notch axis in mediating flow-induced changes in SMC growth. It is hoped that our research will provide valuable new information central to the understanding of the novel role for Hh/VEGF/Notch signaling in vascular biology, and thus further our knowledge of the critical role of this signaling cascade in the etiology of vascular disease. Understanding these molecular mechanisms, which underlie vascular remodeling, should enable the design of novel therapies for cardiovascular disease, which is clearly of major significance and clinical importance. In addition, our research also focuses on Abdominal Aortic Aneurysm (AAA) development and the contributory role of a novel Hh/Notch/ TGF-β signaling cascade. This research, which involves collaboration with the Vascular Surgery Group, hopes to identify possible biomarkers and therapeutic targets of AAA which is the 10th leading cause of death in white men aged 65 to 74 years in the United States.
According to the American Heart Association, heart attacks and other forms of cardiovascular disease result in approximately 800,000 deaths annually in the USA, accounting for 36% of the nations total mortality. Epidemiologic studies from more than 20 countries associate moderate consumption of alcohol with a reduced incidence of cardiovascular disease, while conversely, chronic alcohol abuse is associated with increased mortality. The question of how alcohol causes its effects is of great interest, yet very little is known to date about how it acts mechanistically, particularly in the vasculature. Over the last decade our laboratory has focused on this question at a cellular and molecular level.
We investigate vascular effects of ethanol (i.e., the alcohol found in alcoholic beverages) and of red wine polyphenols (e.g., resveratrol, quercetin) using cultured human cells in vitro in combination with in vivo models of vessel remodeling and atherosclerotic plaque. The role of mechanical forces associated with pulsatile blood flow and their critical effects on vascular cell biology and function in the context of cardiovascular disease is also of great interest to us and we utilize state-of-the-art techniques to determine signal transduction pathways that are modulated in vascular cells exposed to controlled conditions of shear stress, pulse pressure and stretch.
We have previously reported that while ethanol stimulates the growth and migration of endothelial cells (EC), it inhibits vascular smooth muscle cell (SMC) growth and migration. We have also shown that daily moderate alcohol feeding markedly inhibits intima-media thickening and plaque development following carotid ligation injury in the mouse. Endothelial dysfunction and/or loss is widely recognized as one of the early alterations in the vessel wall preceding the development of atherosclerotic plaque. Subsequently, the growth and migration of SMC are key processes in atherogenesis, contributing to intima-medial thickening and lumen narrowing. Given the key role of both EC and SMC in the pathophysiology of atherosclerosis, the opposing effects of ethanol on these vascular cells might be considered synergistically cardioprotective and are thus of considerable clinical interest. Our recent studies implicate the Notch signaling pathway in mediating both ethanol’s promotion of EC proliferation and it’s attenuation of SMC proliferation. We are currently investigating precisely how ethanol might differentially control Notch signaling in these cells with a focus on lipid-raft trafficking of γ-secretase subunit components, and GSK3ß regulation. A novel role for the ‘vascular protective’ transmembrane protein Nogo-B in mediating alcohol’s differential effects on vascular cell Notch signaling is also under investigation. It is hoped that our studies will yield new information enabling the design of innovative targeted therapies for cardiovascular disease which remains a leading cause of death and disability.