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Project Investigators

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.

Differential Control of Metabolic and Cardiovascular Functions by Leptin

Jussara M. do Carmo, PhD, Assistant Professor 
Department of Physiology and Biophysics
Leptin plays a key role in the regulation of cardiovascular and metabolic function through its central nervous system effects on appetite, energy expenditure, blood pressure (BP) and sympathetic nervous system (SNS) activity. Despite leptin levels being elevated in obesity its ability to suppress appetite is markedly attenuated, whereas its effect to increase SNS activity and BP are maintained, suggesting that obesity is associated with "selective" leptin resistance.
The mechanisms for this differential regulation of appetite, SNS activity, and BP, however, are still unclear. We also observed selective leptin resistance when ambient temperature was reduced from thermoneutral zone (TNZ, 30oC or 86oF) to 15oC; i.e. chronic leptin infusion at 15oC (59oF) markedly raised BP and heart rate (HR) while the reduction in food intake was only transient . Conversely, at TNZ leptin infusion caused pronounced and sustained suppression of food intake but failed to raise BP and HR.
We hypothesize that activation of intracellular signaling pathways activated by the leptin receptor (STAT3, IRS2 and SHP2) may contribute differently to the multiple actions of leptin at TNZ compared to colder temperatures. We will use integrative approaches employing molecular, genetic, and integrative physiological and pharmacological tools to test our hypothesis. We will use novel genetically modified mouse models in combination with sophisticated methods for measuring integrative cardiovascular and metabolic functions that will provide important new insights into fundamental mechanisms controlling energy homeostasis, SNS activation, and BP as well as the mechanisms by which leptin exerts divergent control of cardiovascular and metabolic functions.

The Role of MMPs in the Progression of Diabetes-Induced Renal Injury

     williams--photograph.jpgJan M. Williams, PhD, Associate Professor
Department of Pharmacology & Toxicology
The early stages of diabetes are characterized with increases in arterial pressure being transmitted to the kidney leading to elevations in glomerular capillary pressure (Pgc) which eventually cause development of proteinuria and renal injury. However, the mechanism by which increases in Pgc promote diabetic nephropathy (DN) is unclear. The Dahl salt-sensitive (SS) rat is a low-renin, salt-sensitive dependent model of hypertension that is highly susceptible to development of hypertension-induced renal disease when challenged with a high salt (HS) diet. In preliminary experiments, we observed that induction of diabetes with streptozotocin (STZ) in SS rats produced severe proteinuria with renal histological abnormalities characteristic of patients with DN. Matrix metalloproteinases (MMPs) have emerged as potential downstream candidate genes that contribute to the development of focal glomerulosclerosis and renal interstitial fibrosis.
In other preliminary studies, we observed that the activity of MMP-2 and -9 in the renal cortex were increased during the development of diabetes-induced renal injury in SS rats treated with STZ. These findings led to our current hypothesis that hyperglycemia induced by STZ in SS rats promotes the development of diabetic nephropathy by altering renal hemodynamics leading to an increase in the transmission of pressure to the glomerulus (Pgc) and initiating a cascade of events that increases MMP activity and promotes the development of proteinuria, renal fibrosis and progressive renal disease.
The novel aspects of these studies are that they will evaluate the use of the MMP inhibitor, XL784, on the development of renal injury in our diabetic model of renal injury(STZ-SS rat) and will take advantage of the Zinc-finger (Zn) knockout strategy to test the role of MMP-2 (Zn MMP-2 KO SS strain)in the development of renal disease in STZ-SS rats. These studies will provide compelling evidence that MMPs play a critical role in the progression of renal injury associated with diabetes and that MMP inhibitors of may emerge as a treatment for DN.

The Role of Nocturnal Home Blood Pressure and Cardiac Structure and Function in Hypertension

Yuichiro Yano, PhD, Assistant Professor 
Department of Preventive Medicine        
Blood pressure (BP) measurements during sleep (i.e., nocturnal BP) are important to identify persons at high risk of developing adverse cardiac remodeling and heart failure (HF). This need is particularly pressing in overweight/obese hypertensive patients, who have considerably greater risk for cardiac hypertrophy and HF. However, assessment of nocturnal BP in clinical practice is challenging due to the methodological difficulties of 24-hour ambulatory blood pressure monitoring (ABPM).Technological advances now allow for measurement of nocturnal BP at home using portable devices that automatically take BP readings during sleep. This relatively new methodology has been tested in Asian and European countries and found comparable to ABPM. However, culture, living environment, and adherence to medical advice or treatment may differ among nations and races. Information currently is limited regarding the clinical relevance and feasibility of measuring nocturnal BP using home BP devices among hypertensive patients in the U.S., and whether prior results from Asian and European countries are broadly generalizable to U.S. patient populations is unknown.
Our broad goal for this project is to assess the feasibility and clinical relevance of obtaining nocturnal BP measurements in a home setting and using these measurements to identify associations with cardiac structure and function in hypertensive patients. We will test the central hypothesis that measuring nocturnal BP by home BP devices in a U.S. hypertensive population to determine risk for cardiac hypertrophy and diastolic dysfunction is clinically useful. We will also determine whether adjustment for nocturnal home BP attenuates the relationship between adiposity and cardiac hypertrophy and diastolic dysfunction. Our biracial study sample (n=55) will be recruited from hypertensive patients who receive regular outpatient treatment at University of Mississippi Medical Center (UMMC) Heart Center (half will be obese, defined as BMI 30kg/m2)