My research focuses on discovery of the physiological adaptations to hypoxia and to identify the mechanism(s) by which hemoglobin or other oxygen carrying proteins induce either a positive or negative effect on the pulmonary or systemic vasculatures. Understanding the hemoglobin protein, oxygen delivery, nitric oxide biology, oxidative stress and inflammatory signaling pathways on endothelial cells is critical to this area of work. Areas of interest to this central theme include: Investigating mechanisms that cause high altitude illness, pulmonary arterial hypertension, endothelial cell dysfunction, vascular adhesion and strategies for Nrf2-induction to control oxidative stress.
High Altitude Physiology:
Soldiers and Special Operation Forces have always been exposed to environmental factors and many areas of conflict are being waged at moderate to high altitude (8,000 -14,000 ft). Highly specialized rapid transport vehicles have increased the efficiency with which key military personnel are inserted into these regions of conflict, which results in an increased incidence of high altitude illnesses. Over the past 6 years our research group has engineered hemoglobin based oxygen carriers (HBOC) and investigated Hypoxia inducible Factor (HIF) as well ass Nuclear Factor Erythroid-2 Related Factor-2 (Nrf2) regulated proteins to understand adaptations to high altitude. We are currently focused on drug development for the treatment of high altitude illnesses, which involves screening candidate compounds for: (1) desired method of actions in cell based systems; (2) evaluating hemodynamic, vascular and exercise response effects of compounds in animal models and; (3) selecting promising candidate for human clinical safety and efficacy testing toward attenuating altitude illness and improving exercise performance. Our group currently has four candidate drugs in the process of human trials testing safety and efficacy.
Hemoglobin Toxicity and Hemolytic Disease Syndromes:
Hemolytic diseases, such as sickle cell disease are devastating illness that affects millions of people world wide. Each of these patients suffers a broad spectrum of pulmonary and systemic vascular diseases caused by red blood cell hemolysis, high plasma levels of cell free hemoglobin (Hb), endothelial cell dysfunction, and tissue hypoxia. As the consequence of these major health issues patients often have a life expectancy of only 50 years. A leading cause of death in sickle cell disease is Pulmonary Arterial Hypertension (PAH). Plasma Hb is a key contributor to PAH. Unfortunately, the precise mechanisms responsible for Hb-induced endothelial cell injury, leading to PAH, are unknown. Strategies to elucidate these mechanisms are thus essential to guide the development of new therapies to protect the vascular endothelium from Hb insults in order to increase the quality of life and life span of people affected hemolytic disease syndrome.
Currently we are focused on investigating the interface between free hemoglobin and the endothelium. The endothelium is the first vascular target for free hemoglobin and is exposed to the worst of hemoglobin’s’ toxic effects, which lead to endothelial cell dysfunction and is pivotal to the vascular disease. Over the past several years, we have built a team and network of investigators committed to solving this problem. To this end, we have developed novel methodology utilizing micro and syringe pump technology to investigate the effects of chronic exposure to hemoglobin and the development of vascular and organ dysfunction in rodents. Additionally we have developed in vitro microfludic flow assays to determine how free Hb interfaces with endothelial cells and causes blood cell adhesion. Recently we have discovered that it is not necessary for Hb to scavenge nitric oxide to create a pro-inflammatory environment and cause vascular disease, and that Hb can activate NFb and HIF transcription factors via a MyD88 dependent signaling pathway independent of its pro-oxidant effects resulting in increased endothelial permeability. MyD88 is an important protein associated with pro-inflammatory signaling receptors.
Keywords: Hemoglobin, Hypoxia, High altitude, HIF, ROS, NF-kB, Nrf2, pulmonary vascular disease.