Interdisciplinary Ph.D. In Biomedical Sciences

Drs. Kim Tran, Eric Wauson, Sarah Clayton and Dan Christian, Department of Physiology and Pharmacology

Hypertension is a leading cause of cardiovascular disease. The G Protein-coupled Estrogen Receptor 1 (GPER, aka GPR30) has been associated with many protective actions in the cardiovascular system. However, therapeutic applications thereof are currently unavailable for cardiovascular disease. We have identified unique interactions between GPER/GPR30 and molecular structures that regulate blood pressure. Based on these interactions, we have developed new peptides with unique effects that are promising for the management of hypertension and protection of vascular functions. This project aims at assessing the therapeutic applications of these novel peptides using a combination of molecular, biochemical, and biophysical approaches and studies in wildtype and knockout animal models.

Drs. Kim Tran and Eric Wauson, Department of Physiology and Pharmacology

Macroautophagy (autophagy) is a catabolic process that degrades nonfunctional or unused cellular components to maintain tissue homeostasis. Derangement of autophagy is a major cause of cardiovascular diseases. We have identified molecular actions of the G Protein-coupled Estrogen Receptor 1 (GPER, aka GPR30) that are critical for multiple steps in cardiac autophagy. This project aims to delineate the mechanisms whereby GPER/GPR30 regulates cardiac autophagy under normal or stressed conditions, with the goal of developing novel therapies that optimize cardiac functions. In addition, we aim to develop novel single and multiplexed sensors for monitoring autophagic flux and related intracellular signals that operate in autophagy. We combine multiple approaches, including molecular biology, in vitro biochemistry, biophysical studies, and animal studies in wildtype and GPER/GPR30 knockout models.

Drs. Eric Wauson and Kim Tran, Department of Physiology and Pharmacology

Inflammation is involved in many aspects of cardiovascular disease. Activation of the NLRP3 inflammasome and secretion of cytokines play essential roles in inflammatory responses. While estrogen has been shown to play important roles in inflammation, the mechanisms and therapeutic applications of these actions are unclear. We have identified unique effects of the G Protein-coupled Estrogen Receptor 1 (GPER, aka GPR30) on the activation of NLRP3 and production of cytokines. This project aims to delineate the molecular mechanisms whereby GPER/GPR30 regulates cardiac inflammatory responses, with an overall goal of developing new tools for the management of inflammation in the heart. We combine molecular and cellular approaches, coupled with studies in wildtype and GPER/GPR30 knockout animals.

Dr. Maria Barnes, Department of Biochemistry and Nutrition

Greater than 75% of post-menopausal women are hypertensive. These women are more likely to have uncontrolled hypertension, suggesting that the efficacy of drug treatment or hormone replacement therapy is inconsistent in the management of their blood pressure. The overarching goal of our laboratory is to identify mechanisms that can be exploited for effective treatment of hypertension in post-menopausal women. We utilize in part in vivo (animal models) and in vitro (neuronal cell cultures) models and a variety of molecular and histological techniques to test our novel hypotheses.

Dr. Maria Barnes, Department of Biochemistry and Nutrition; Dr. Francesca Di Sole, Department of Physiology and Pharmacology and Dr. Victor Babich, Mercy College of Health Sciences

Obesity represents a major risk factor for hypertension and raises blood pressure by impairing renal salt handling and pressure natriuresis, causing volume expansion via activation of the brain-kidney axis. Dietary guidelines for obesity typically focus on caloric nutrients, while intake of noncaloric nutrients such as salt is rarely discussed. However, high salt intake is associated not only with increased risk of hypertension but also with the development of obesity. The mechanisms of this salt effect are largely unknown. This study aims to identify mechanisms activated by the brain-kidney axis to control the effect that salt has on increasing the risk for developing hypertension in obesity and provide insights into potential interventional approach against hypertension associated with obesity.

Dr. Yujiang Fang, Department of Microbiology and Immunology

Interleukin-39 is the most recent member of the interleukin-12 cytokine family. It is composed of a heterodimeric chain-pairing of IL-23p19 and EBI3. IL-39 has been studied only on SLE. Its role in the development and progress of neoplasia has not been investigated yet. Prostate cancer is the most common cancer in males, and many brain tumors are lethal. We previously reported that IL-39 significantly inhibited proliferation and promoted apoptosis of bladder cancer, and IL-37 was a promising radiosensitizer for prostate cancer. The purpose of this study is to investigate 1) if IL-39 has any direct effects on proliferation, apoptosis and senescence of prostate cancer and brain tumors by using different tumor cell lines, 2) if it could act as a potential radiosensitizer for prostate cancer and brain tumors and 3) the potential molecular mechanisms. Such a study might provide new strategies for immunotherapy and help enhancement of radiation therapy for prostate cancer and brain tumors.

Drs. LiLian Yuan, Sarah Clayton and Dan Christian. Department of Physiology & Pharmacology. 

We are interested in mechanisms of neuronal connectivity and plasticity, how environmental and genetic factors modulate these processes, and how they are altered in human diseases. A combination of animal models and behavioral, molecular, and bioinformatic approaches will be employed for the following projects.

1. Exercise as an active lifestyle (Drs. LiLian Yuan, Sarah Clayton, and Dan Christian, Department of Physiology & Pharmacology). Our overarching objective is to unravel the mechanisms that motivate voluntary exercise behavior, delve into the impact of exercise on the central nervous system and ultimately harness its numerous benefits.
2. Bidirectional communication between the brain and the gut microbiota (Dr. LiLian Yuan, Des Moines University, and Dr. Matt Rusling, Walter Reed National Military Medical Center). We investigate the gut microbiome's role in mood (dys)regulation resulting from chronic stress. We also develop innovative analytical tools for gut microbiome research.
3. Ketamine as a breakthrough antidepressant (Dr. LiLian Yuan). We investigate ketamine's mechanisms of action. This knowledge is pivotal in identifying novel therapeutic targets that may pave the way for developing a new generation of fast-acting antidepressants with minimal or no adverse effects.

Drs. Noah Marcus, Sarah Clayton and Francesca Di Sole, Department of Physiology and Pharmacology, Des Moines University, Dr. James Lang, Iowa State University, and Dr. Rodrigo Del Rio, Kansas University Medical Center

Sleep apnea, a condition characterized by periodic cessation of breathing during sleep, is commonly underdiagnosed in females and has been observed to be highly prevalent (39%) in females with androgen excess polycystic ovary syndrome. Both sleep apnea and PCOS are associated with multi-morbidity, most notably obesity, development of metabolic syndrome and hypertension. In addition, one recent study has identified PCOS as a significant independent risk factor for development of chronic kidney disease. Sleep apnea is observed in 50-60% of patients with CKD and is independently associated with increased risk of cardiovascular events, end stage renal disease and mortality. Our laboratory's long-term goal is to better understand the pathophysiology of hypertension and renal dysfunction in patients with SA. Current projects in the lab are focused on determining the autonomic, hemodynamic, and biochemical mechanisms by which SA may contribute to renal tissue hypoxia in PCOS. Our central hypothesis is that renal tissue hypoxia derives from synergistic changes in autonomic function, reductions in oxygen delivery and increased renal oxygen consumption. We believe that autonomic and hemodynamic dysregulation are a result of biochemical changes that cause oxidative stress and uncoupling of renal nitric oxide synthase. Understanding determinants of renal tissue oxygenation in this model will provide a deeper understanding of the development of hypertension and CKD in women with SA and inform condition-appropriate treatment for PCOS patients with SA.