E. Leila Jerome Clay, MD
Dr. Clay is establishing her research in sickle cell disease where she studies the mechanistic contribution of vitamin D deficiency, bone disease and its effects of disease manifestation. Her primary professional objective is to translate her clinical research to the field. In 2014, Dr. Clay became one of four scholars of the NIH funded Hematology and Translational Research Core (HTRC). She is using this funding to further research the mechanism of vitamin D, endothelial dysfunction and pain in sickle cell disease. She hopes to use those data collected for further support in bone disease and sickle cell disease. With the support of the HTRC grant, she is also enrolled in a Master’s of Translational and Clinical Research.
Joyce Gonzales, MD
Assistant Professor, Department of Medicine-Pathology
The leading cause of sudden death and hospitalization in patients with sickle cell disease (SCD) is acute chest syndrome (ACS). Although both infectious and non-infectious causes for ACS have been suggested, the pathophysiology of the disease remains elusive and often ill-defined, even at autopsy. Standard therapy of ACS remains supportive and includes transfusion (exchange or simple), use of bronchodilators and mechanical ventilation. We hypothesize that a contributing factor in ACS, however, is a well-documented increase in thrombin generation, even in patients at steady state. The “kindling” of thrombin promotes baseline platelet activation and likely contributes to endothelial cell dysfunction via the thrombin receptors (PAR 1-4). In fact, thrombin is a powerful inducer of endothelial cell hyperpermeability, which is a hallmark of ACS. It is therefore postulated that agents that reduce the deleterious effects of thrombin can be therapeutically beneficial. One such agent is low anticoagulant heparin 2-O, 3-O desulfated heparin (ODSH). Our data suggest that the primary site of action of ODSH is a single thrombin receptor, protease activated receptor-1 (PAR-1). Since ODSH spares thrombin activity, its action at the receptor would maintain the important fibrin generation activities of thrombin, but would blunt the EC and platelet activation properties. The focus of my research is to accomplish the mechanism and evaluate the pre-clinical efficacy of ODSH as a therapeutic agent for ACS in patients with SCD.
Umapathy Siddaramappa, PhD
Assistant Professor, Department of Medicine-Hematology/Oncology
Our goal in the HTRC project is to develop β-nicotinamide adenine dinucleotide (β-NAD) as a treatment for SCD which mediates protective mechanisms against bacterial toxin lipopolysaccharide (LPS)-induced EC barrier dysfunction. We hypothesize that β-NAD protect the myosin light chain phosphatase (MLCP), an enzyme plays a crucial role in the maintenance of EC barrier function, and its cytoskeletal targets (ezrin, radixin, and moesin, ERM and Caldesmon, CaD) against LPS toxicity. To test this hypothesis, we will use primary EC from human as well as the preclinical transgenic sickle cell mouse model. To directly link the involvement of MLCP and its cytoskeletal targets in β-NAD-induced protection against LPS, we will deplete by siRNA/shRNA the MLCP target subunit, MYPT1 and the cytoskeletal proteins individually or in combination and measure the EC barrier function using electric cell-substrate impedance sensing (ECIS) instrument with LPS +/- β-NAD. Next, we will use cDNA containing plasmids specific for MLCP subunits and study their effects on EC barrier function. The immunocytochemistry and the western blot experiments will be performed to determine the phosphorylation/dephosphorylation events using LPS +/- β-NAD. We will then perform a pilot study to test whether β-NAD improves sickle cell mice survival against LPS-induced mortality. The positive outcome of these innovative studies will determine β-NAD mediated protective mechanisms and help develop a potential therapeutic intervention for ACS in patients with SCD.
Xingguo Zhu, PhD
Assistant Research Scientist, Department of Pediatrics-Hematology/Oncology
Sickle cell disease (SCD) is the most common inherited genetic disorder affecting about 100,000 African Americans in the United States. Dr. Zhu’s project involves the roles of nuclear factor erythroid 2–related factor 2 (NRF2) as an emerging regulator of cellular resistance to oxidative stress in SCD. Dr. Zhu is investigating the ability of the NRF2 inducers dimethyl fumarate (DMF; Tecfidera) in alleviating the symptoms of SCD through multiple signaling pathways. The goal of Dr. Zhu’s project is to repurpose DMF as a treatment option for SCD. He will test the overarching hypotheses that NRF2 is activated by DMF followed by subsequent activation of fetal hemoglobin to levels relevant for the treatment of SCD. Studies will be conducted in primary erythroid cells and a unique sickle cell/Nrf2 knockout mouse model. Dr. Zhu will characterize the molecular role of NRF2 and its DNA binding partner small Maf proteins in human gamma globin gene regulation during erythropoiesis. He will determine changes in chromatin structure including epigenetic DNA methylation in the presence of NRF2 binding after DMF in regulating the fetal gamma globin genes.