Area of Investigation

Vascular biology of hemoglobin disorders; Microcirculation; Oxidative stress; Blood cell-endothelium interaction; nitric oxide (NO); non-NO vasodilators; Hypoxia-inducible factor-1alpha.

Brief Description

Our laboratory focuses on the mechanisms of vascular dysfunction in hemolytic disorders such as sickle cell disease and thalassemia.   In our studies, we have used an integrated physiological approach combining intravital microscopy and hemodynamic measurements in single microvessels with cellular, biochemical and molecular biology techniques.  Our studies are directed towards understanding mechanisms that contribute to endothelial abnormalities, altered microvascular regulation and abnormal blood cell-endothelium interactions in these hemolytic disorders.  One major goal is to dissect the role of hemolysis and oxidative stress in altered vascular function.  Our studies have revealed that NO inactivation in these hemolytic disorders results in NO resistance as NO is consumed and/or inactivated by cell-free plasma heme and oxidative stress.  We have also discovered that NO depletion is associated with induction of non-NO vasodilators resulting in altered vascular reactivity and hemodynamic adjustments.  On the other hand, therapies designed to reduce hemolysis and oxidative stress result in marked increase in NO bioavailability, reduced expression of non-NO vasodilators and improved microvascular function.  Lately our laboratory has been exploring the role of hypoxia-inducible factor-1alpha in vascular regulation in sickle cell disease.

The second major goal of our research is directed at mechanisms by which sickle red cell interact with vascular endothelium leading not only to vascular endothelial damage, apoptosis and platelet activation, but also to vaso-occlusion.  Our laboratory has been in the forefront in defining predominant adhesion mechanisms involved in this pathologic cell adhesion.  We have developed new therapeutic approaches that target intercellular adhesion molecule-4 (ICAM-4) expressed by sickle red cells and its endothelial receptor alphaV beta3 integrin.

To accomplish our objectives, we have access to a variety of transgenic mouse models, including transgenic sickle mice expressing exclusively human sickle hemoglobin, sickle mice expressing varying levels of fetal hemoglobin, beta-thalassemic mice and sickle mice deficient in hypoxia-inducible factor.  We also use artificially perfused microvasculature to investigate the effect of specific factors. 

Funding

Our research has been supported by grants from NIH and American Heart Association.

International/National recognition

1. Our published work has been recognized at both national and international levels.   In the year 2008, Dr. Kaul has been invited as a featured or plenary speaker in the following conferences:
2. Invited guest speaker at the annual meeting of French Society of Hematology, Paris, March 20-22, 2008. 
   Title of the talk:  Mechanisms of sickle red cell-endothelial interactions and development of synthetic peptides with inhibitory activities.
3. Featured speaker at the International Conference on Adhesion Molecules 2008, Co-organized by INTS and Pasteur Institute, Paris, France. July 3-4, 2008. 
   Title of the talk: Sickle red cell adhesion: many issues and some answers.
4. Plenary speaker at the Workshop on Vasculopathy in Sickle cell Disease organized at the National Institutes of Health, USA, in conjunction with 2008 Annual Sickle Cell Clinical Research Meeting, August 25-29, 2008. 
   Title of the talk:  Nitric oxide resistance in sickle cell mouse.