Sickle cell disease (SCD) is an inherited hematological disorder. The disease affects millions of people worldwide including individuals in the United States, Saudi Arabia, India, several countries in South America and most profoundly in sub-Saharan Africa. SCD is defined by the presence of Hemoglobin S (HbS) as the primary hemoglobin species that drives a multifaceted pathophysiology characterized by chronic vasoocclusion, hypoxia, reduced nitric oxide (NO) bioavailability and inflammation. Pulmonary dysfunction is a major clinical burden in SCD; it often leads to a serious pulmonary-vascular complication called Acute Chest Syndrome (ACS). ACS is the second most common cause of hospitalization and is the leading cause of referral to intensive care units, and is associated wit increased mortality in SCD. To date, only one FDA approved drug exists to treat this disorder, therefore it is imperative that novel therapeutics are developed to attenuate pulmonary vascular clinical complications associated with SCD. Our objectives for this proposal are to: (a) define the Nrf2 mediated tissue- and the drug-specific inductions of the antioxidant and detoxification defense specifically in the hematopoietic system and the pulmonary vascular endothelium, (b) assess if prophylactic pharmacological activation of Nrf2 is an effective therapeutic strategy to slow down organ damage in SCD, and (c) identify the drug specific molecular mechanism that facilitate efficacy toward the attenuation of organ damage in SCD. We hypothesize that: Endothelial Nrf2 activation suppresses chronic pulmonary dysfunction in sickle cell disease. We will test this hypothesis with the following two aims: (1) Determine the drug specific spatiotemporal induction of Nrf2 regulated antioxidant and cytoprotective enzymes in the hematopoietic system and the pulmonary vascular endothelium, and (2) determine whether activation of Nrf2 will attenuate pulmonary dysfunction in sickle cell disease.
The aims proposed address the key shortcomings in SCD drug therapy and evaluates a drug and tissue specific prophylactic approach to pharmacologically induce cytoprotection in SCD. This proposal will accomplish the candidate's primary goal for this fellowship, to become a productive independent investigator in basic and translational biomedical research. The training, mentoring, and didactic goals of this fellowship are specifically designed so that the candidate can complete the scientific aims described in this application, while developing a technical and analytical repertoire to become a leader in biomedical research.
Chronic inflammation and oxidative stress cause pulmonary dysfunction in sickle cell disease. Nrf2 induction is the primary cellular detoxification response o oxidative stress and electrophilic signaling, and preliminary studies in our lab demonstrate that Nrf2 signaling contributes to the pathophysiology of sickle cell disease. We propose studies that identify the Nrf2 mediated tissue- and the drug-specific inductions of the antioxidant and detoxification defense as a first step to attenuate organ damage in SCD.
