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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.


Project I - Diabetes, Cerebral Vascular Dysfunction and Cognitive Impairments

Fan Fan.jpgFan Fan, MD, MS
Assistant Professor
Department of Pharmacology & Toxicology
Diabetes mellitus (DM) is one of the leading risk factors for cerebrovascular disease (CVD) and cognitive impairment, especially at the late stage with mild hypertension, but the underlying mechanisms have not been fully elucidated. Dementia is one of the major causes of disability, and the fifth leading cause of death in the elderly in the US. The annual cost for treating dementia is $159 billion, and is projected to rise to $511 billion by 2040. There is an urgent need to understand the mechanisms involved and for development of new therapeutic strategies to delay the onset and progression of these devastating diseases. Mounting evidence suggests that DM is associated with impaired endothelial function and neurovascular coupling, and elevated myogenic tone and reactivity at an early stage. The enhanced myogenic tone and activity in DM decline with age, however, it is to be determined whether CBF autoregulation is impaired in vivo and if it plays a role in the development of dementia in hypertensive DM.
This proposal builds upon our preliminary data indicating that the myogenic response and CBF autoregulation are impaired in response to elevated cerebral perfusion pressure in our novel diabetic rat models. Following development of mild hypertension, DM rats exhibit BBB leakage, inflammation, vascular remodeling, neurodegeneration and cognitive dysfunction. Importantly, forced dilatation of middle cerebral artery (MCA) and CBF autoregulatory breakthrough occurring at lower pressure are only observed in older DM rats with long standing hyperglycemia and after they have developed mild hypertension. We also observed that the neurodegeneration is associated with elevated expression of beta amyloid (Aβ 1-42) and pTau (S416) in the brain in mild hypertensive DM rats, suggesting that Alzheimer-like neuronal cell death pathways are also activated. The enhanced expression of GFAP and IL-1β in hypertensive DM rats indicate that glial activation and inflammation may play a role in linking aging, diabetes and cognitive deficits. In translational studies, we found that cognitive impairment in elderly participants in a largely diabetic ARIC-NCS population may be associated with impaired CBF autoregulation.
This proposal will use our novel non-obese types 1 and 2 DM rat models, which do not exhibit severe lipid and other metabolic derangements normally associated with DM, to investigate whether impaired myogenic response and CBF autoregulation contribute to cognitive impairment, and whether the synergistic effects of DM and hypertension promote development of cognitive deficits. We will also use luseogliflozin to normalize plasma glucose levels by inhibition of renal sodium-glucose co-transporter 2 (SGLT2) without altering blood pressure in our DM models, as we previously reported, to determine the role of hyperglycemia in cerebral vascular dysfunction and dementia. This proposal will address one of the significant gaps in this field by investigating whether chronic hyperglycemia, especially in association with hypertension, causes impairment of CBF autoregulation and dementia using our novel diabetic rat models.

Project II - The Role of Leptin in Autoimmune-Associated Hypertension

Erin Taylor.jpgErin Taylor, PhD
Department of Physiology & Biophysics     
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.

Project III - Physiological and Molecular Metabolic Consequences of Fetal Hyperglycemia

Gibert,-Yann.jpgYann Gibert, PhD
Associate Professor 
Department of Cell and Molecular Biology

Fetal hyperglycemia occurs when the developing fetus is exposed to high levels of glucose. For example in humans, this is the case when the mother has diabetes. Fetal hyperglycemia is linked to health complications for the fetus, including preeclamsia, fetal macrosomia and even fetal death. In addition, fetal hyperglycemia also increases the risk for the individual to develop a variety of diseases later in life. Adults exposed to fetal hyperglycemia are more susceptible to obesity, insulin resistance, type 2 diabetes, cardiovascular diseases and several metabolic syndromes. To date, the physiological and molecular mechanisms that underlie the link between fetal hyperglycemia and the adult sequelae are poorly understood. The central goal of this project is to examine the physiological and molecular basis of metabolic diseases in adults exposed to high levels of glucose only during embryogenesis. To accomplish this goal, we have recently developed a zebrafish model of fetal hyperglycemia. Zebrafish offers several advantages to complete this project. From a biological point of view, zebrafish embryos have the unique feature of being a “closed system” i.e for the first 5 days of development, the embryo solely relies on the yolk sac reserved deposited by the mother during ovulation and no energy exchange happens with the exterior world prior the end of embryogenesis. Therefore, in zebrafish we can directly expose the embryos to known concentration of glucose. Thus, specific aim 1 will test the hypothesis that fetal hyperglycemia leads to an increase in BMI, fat mass and insulin resistance in adults fed normal diet. Specific aim 2 will test the hypothesis that embryonic hyperglycemia increases glycolysis while decreasing β-oxidation in embryos and in adults. Specific aim 3 will test the hypothesis that fetal hyperglycemia causes hyperlipidemia and non-alcoholic fatty liver disease in adults. Specific aim 4 will test the hypothesis that embryonic hyperglycemia increases the levels of circulating lipids and causes atherosclerosis later in life. Successful completion of this proposal will lead to a better understanding of the physiological and molecular consequences of fetal hyperglycemia and will help in defining strategic therapeutic interventions to prevent the development of metabolic diseases in adults exposed to glucose during embryogenesis.