Weintraub - Basic Science Project

Obesity is a shared risk factor for cardiovascular disease (CVD) and cancer, with insulin resistance and inflammation postulated to be key underlying mechanisms. African Americans exhibit more pronounced insulin resistance and inflammation compared with non-Hispanic Caucasians, and a higher prevalence of hypertensive disease, peripheral artery disease (PAD) and cancer mortality. Understanding the basis for these differences in disease prevalence may help improve prevention and treatment of CVD and cancer for all individuals. Here, we focus on variability in the Duffy antigen receptor for chemokines (DARC) gene. DARC is most highly expressed on erythrocytes (RBC), where it controls inflammation by serving as a decoy chemokine receptor and a chemokine 'buffer-sink.' ~70% of African Americans carry a mutation in the DARC promoter, leading to loss of its expression on RBC and aberrant function of key inflammatory chemokines such as monocyte chemoattractant protein (MCP)-1 that may promote CVD and cancer. Published and preliminary data indicate that global DARC knockout (KO) mice exhibit enhanced susceptibility to obesity-related adipose inflammation and metabolic disease, higher blood pressure, and increased tumor growth/vascularity. We hypothesize that loss of DARC on hematopoietic cells disrupts chemokine regulation, thereby predisposing to obesity-related metabolic disease, hypertension, PAD, and tumor angiogenesis, all of which are common in African Americans. Using a novel DARC floxed mouse created by our lab, Aim 1 will test the hypothesis that loss of DARC on hematopoietic cells promotes insulin resistance and obesity-related metabolic disease. In Aim 2, we will test the hypothesis that loss of DARC promotes hypertensive disease via an MCP-1 dependent mechanism. We will examine salt sensitivity and stress responses, which are more pronounced in African Americans versus Caucasians. Also, we will determine the impact of orchiectomy on blood pressure and vascular stiffness in aged wild type and DARC KO mice as a model of androgen deprivation therapy for prostate cancer. In Aim 3, we will test the hypothesis that DARC gene deletion on hematopoietic cells impairs ischemia-induced neovascularization while promoting breast cancer cell growth and tumor angiogenesis in both lean and obese mice. These studies will provide novel insight into mechanisms of obesity-related disparities in CVD and cancer.