The CMDRC supports three major research projects and several pilot research projects of junior investigators who focus on cardiovascular, renal and metabolic diseases, which are the leading causes of mortality and morbidity in the United States, especially in Mississippi which has the highest prevalence in the nation of these diseases.
The CMDRC has assembled a unique team of junior investigators who have previous research experience in obesity, cardiorenal or metabolic diseases, strong records of research productivity, and an excellent scientific background. The team of junior investigators work together in an integrated environment to translate findings from the bench to bedside to significantly impact the epidemic of obesity in the nation. This focused, in-depth research experience promotes continued growth of their research programs and lays the foundation for them to successfully compete for NIH funding.
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disorder characterized by a loss of immunological tolerance and the expansion of autoreactive T and B lymphocytes, leading to the production of autoantibodies. The immune system dysfunction in SLE leads to downstream chronic inflammation and high rates of hypertension, renal injury, and cardiovascular disease. Patients with SLE also have alterations in circulating cytokines, including elevated plasma levels of the adipokine leptin. Leptin is produced by white adipose tissue and has a prominent role in regulating appetite and energy expenditure via its actions in the hypothalamus. However, it also plays a key role in the maintenance and development of inflammation, in part through its direct effects on cells of both the innate and adaptive immune systems.
The central goal of this project is to examine the contribution of leptin mediated immune system activation on the pathogenesis of hypertension in SLE. To accomplish this goal, a clinically relevant model of SLE, the female NZBWF1 mouse, will be utilized. Similar to patients with SLE, the NZBWF1 mouse exhibits hypertension, renal injury, and elevated circulating leptin levels, in addition to prominent immune system dysfunction. Work in animal models of autoimmunity strongly implicate leptin in the pathogenesis of autoimmune disease, but the contribution of leptin to the prevalent hypertension during SLE, and the mechanism by which this occurs is unknown. Thus, specific aim 1 will test the hypothesis that elevated leptin during SLE promotes hypertension by stimulating the expansion of proinflammatory TH1 and TH17 cells and decreasing TREG cells. Specific aim 2 will test the hypothesis that elevated leptin during SLE leads to the development of hypertension by promoting B cell survival and the production of autoantibodies.
To accomplish these aims, we will administer leptin or block leptin signaling, and test the impact on the development of B and T lymphocyte dysfunction and autoimmune-associated hypertension. Because leptin acts both centrally (central nervous system) and peripherally, we will also examine relative contribution of central and peripheral leptin on immune system function.
Obesity and hypertension (i.e. metabolic syndrome) are highly prevalent in patients who experience myocardial infarction (MI). In addition to increasing the risk of developing MI, these risk factors also promote adverse left ventricular remodeling after MI and thus increase the development of heart failure after MI. However, the mechanisms by which obesity and hypertension interact to promote aberrant post-MI outcomes are not well understood. One possible mechanism is through inflammation, in which monocytes/macrophages play key roles. While macrophages are critical for normal wound healing and resolution of inflammation, they can also promote inadequate healing and exacerbate inflammation during chronic disease states. Following MI, monocytes quickly invade the necrotic LV and differentiate into M1 pro-inflammatory macrophages to generate an inflammatory response, then as wound healing progresses differentiate or "polarize" into M2 anti-inflammatory macrophages to resolve inflammation. Immune cell metabolism (immunometabolism) has been identified as a key factor dictating polarization; however, the role of immunometabolism following MI has not been investigated. Cardiac metabolism is impaired by chronic stressors on the heart, such as obesity and hypertension, and these changes in metabolism contribute to disease progression. Thus, the main goal of this study is to identify how obesity and hypertension interact to affect cardiac macrophage polarization and metabolism after MI, and whether manipulating macrophage metabolism can improve post-MI outcomes in metabolic syndrome. To accomplish this goal, mice will be fed a chronic high fat and high fructose (i.e. Western) diet to induce obesity, and hypertension will be surgically induced by abdominal aortic coarctation. Mice will then be given MI by permanent coronary artery ligation. Macrophage polarization and metabolic phenotypes will be assessed by fluorescence activated cell sorting (FACS), RNA-Seq, and glucose and fatty acid oxidation. In Aim 2, mice will be administered 2-deoxyglucose to perturb glucose metabolism and sodium nitrite to enhance mitochondrial fatty acid oxidation. Macrophage phenotypes will be linked to post-MI outcomes such as survival, cardiac function, and cardiac remodeling.