CURRENT RESEARCH PROJECTS
Residential Segregation, Thromboinflammation and Risk of Hypertension
Hypertension is a leading cause of cardiovascular mortality and the leading risk factor for heart diseases and stroke. In the United States (U.S.), 57.1% of Black adults have hypertension compared to 43.6% of White adults. This racial inequity is a major cause of the striking and longstanding Black-White inequity in stroke.
A key determinant of racial inequities in health is structural racism. Structural racism refers to the totality of ways in which societies foster racial discrimination through mutually reinforcing systems of housing, education, employment, earnings, benefits, credit, media, health care and criminal justice. These patterns and practices in turn reinforce discriminatory beliefs, values and distribution of resources. Residential segregation, a geospatial manifestation of racism, is a fundamental driver of health inequities.
Despite this knowledge, research on the impact of residential segregation on risk of incident hypertension is limited . Similarly, studies on biological mechanisms underlying health effects of residential segregation are scarce. Consequently, the proposed research has two aims that will be addressed in the contemporary REasons for Geographic And Racial Differences in Stroke (REGARDS) study. REGARDS is a national longitudinal cohort study in the United States following 30,239 Black and White adults since 2003. It is studying why Black Americans and those living in the Southeast have higher stroke mortality. First, I will comprehensively study effects of five dimensions of residential segregation (evenness, exposure, concentration, centralization, and clustering) on the risk of 9.4-year incidence of hypertension. Second, to develop mechanistic hypotheses, I will identify associations of the same five dimensions of residential segregation with thrombo-inflammatory biomarkers related to risk of hypertension.
Vascular Endothelial Dysfunction and Risk of COVID-19 in a Biracial US Cohort
The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the obvious disruption that COVID-19 has caused, its pathogenesis remains unclear. Evidence is mounting that vascular endothelial dysfunction plays a role in COVID-19 pathogenesis. Under a hypothesis that basal endothelial dysfunction may increase susceptibility to vascular effects of COVID-19, in this pilot study, we will examine the associations of pre-pandemic biomarkers of endothelial dysfunction with risk of severe COVID-19 in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study.
DOCTORAL RESEARCH
Acculturation and Diabetes in African Migrants to the United States
African immigrants are one of the fastest growing communities in the U.S., yet the epidemiology of cardiometabolic diseases in the population is poorly understood. Using mixed methods analysis, my dissertation research focused on acculturation and diabetes in African immigrants in the U.S. Analysis of the 2010-2017 National Health Survey data showed acculturation was associated with higher odds of diabetes, and BMI (adiposity proxy measure) partially explained the association.
Additional interviewing in a qualitative research study of Congolese immigrants, in Minnesota and the DC-Maryland-Virginia (DMV) area, revealed immigration adversely impacted diet, physical activity and stress levels in African immigrants. Though Congolese immigrants sought to maintain their pre-immigration eating habits, their diet in the U.S. was affected by accessibility and cost. Going to the gym was not particularly relevant to Congolese cultures, and reduction in physical activity levels was accentuated by time constraint and weather conditions. Stress increased after immigration and was mainly caused by financial difficulties. The qualitative analysis also showed that contextual characteristics that influenced acculturation in Congolese immigrants included support, gender norms, religious commitment, instability in the Congo, racism, and xenophobia in the U.S.
My dissertation research has implications for diabetes prevention because it sets the stage for culturally appropriate initiatives targeting the cardiometabolic health of African immigrants in the U.S.
M.S. THESIS RESEARCH
The role of TMEM16F in calcium flux, PS exposure and microparticle formation in platelets
In platelets, transmembrane protein 16 F (TMEM16F), an eight-transmembrane protein, is a calcium activated-cation channel highly permeable to calcium. The TMEM16F gene has been shown to be mutated in Scott's syndrome, a rare bleeding disorder characterized by a defect in the scrambling activity of platelets and microparticle generation. In my thesis, I investigated the effect of TMEM16F on calcium signaling, microparticle formation and phosphatidylserine exposure (PS) in platelets under physiological conditions.
First, I investigated whether TMEM16F was required for optimum calcium signaling in platelets. TMEM16F heterozygous (+/-) mouse platelets treated with a combination of thrombin and collagen displayed a significant decrease in calcium entry measured as percent above basal calcium entry compared to the wild-type platelets (p=0.02). Further analysis of calcium entry revealed that there was a delay in store-operated calcium entry (SOCE) for TMEM16F+/- platelets compared to wild type (WT) platelets (p=0.05). To determine whether TMEM16F is required for maximal PS exposure, binding of Annexin V to activated platelets from WT vs. TMEM16F knockout mice (TMEM16F KO) was compared. To measure PS exposure, annexin V binding to platelet surfaces was quantified by flow cytometry. When treated with thrombin and convulxin, there was a significant decrease in maximal annexin V binding achieved by 10μM A23187 of TMEM16F KO platelets compared to the WT (p=0.0005). Microparticle generation from TMEM16F KO platelets compared to WT platelets was also analyzed by flow cytometry. On average, after thrombin and convulxin treatment, there was a significant decrease of the percentage of microparticles over total particles (microparticles and platelets) generated by the TMEM16F KO mice compared to the WT mice (p=0.05). These data demonstrate that TMEM16F regulates calcium influx, PS exposure and microparticle formation in platelets.
Interestingly, when the channel function of TMEM16F was blocked with CaCCinhA01, there was a significant decrease in the calcium influx compared to the untreated platelets (p=0.01) while no significant change was seen in the PS exposure, suggesting that TMEM16F might have two independent functions in platelets: one as a channel and the other as a regulator of the scrambling activity of platelets.
Furthermore, preliminary results of calcium entry analyzed in HEK293T cells and CHOK cells stimulated with ionophore showed an increase in calcium entry when cells transfected with TMEM16F were compared to untransfected cells. However, analysis of the scrambling activity revealed that heterologous expression of TMEM16F was not sufficient to induce PS exposure after treatment with A23187. These results suggest that there are additional mechanisms to promote TMEM16F scramblase activity in platelets.
OTHER (SELECT) PROJECTS
D-dimer and Risk of Incident Hypertension in The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
D-dimer and Risk of Diabetes in the REGARDS Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Study
Causes of Death after Venous Thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study
Leukocyte Count, Adiposity and Diabetes Mellitus in the REGARDS Study
Hemoglobin A1c in Frozen Packed Cell Samples
Thrombo-Inflammatory Biomarkers and D-dimer in the REGARDS Study
ABO Blood Group and Risk of Severe COVID-19 in Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study and Trans-Omics for Precision Medicine (TOPMed) program
Harmonizing Individual-Level Racism to Inform Racial/Ethnic Inequities in COVID-19 Outcomes Across the Collaborative Cohort of Cohorts for COVID-19 (C4R) Research