Interdisciplinary Ph.D. In Biomedical Sciences

Dr. Vanja Duric, Department of Physiology and Pharmacology

Chronic stress can significantly diminish the ability of the central nervous system to regulate both neurological and systemic stress responses required to maintain normal body functions. Clinical depression, anxiety and other psychiatric symptoms are commonly present in patients with different chronic systemic diseases such as chronic pain or kidney disease. We are interested in studying neural mechanisms underlying stress-induced interruption of the brain’s ability to communicate with and regulate the function of peripheral organ systems, especially the brain-kidney crosstalk. Through utilization of a variety of cell/molecular and pharmacological approaches in combination with animal models (e.g., chronic pain, depression/anxiety, chronic kidney disease), the overall goal of this interdisciplinary research is to aid the development of more effective treatment, diagnostic and prevention strategies for management of not only depression, but also mental health comorbidities associated with different systemic illnesses such as chronic pain and kidney disease.

Dr. Elitsa Ananieva and Dr. Maria Barnes, Department of Biochemistry and Nutrition

Progress in cancer immunotherapy raised hopes that patients diagnosed with hematological malignancies will experience long-term control or eradication of the disease. However, for many patients the cancer immunotherapies have been unsuccessful due to substantial drug resistance, side effects and low remission rates. In addition to that our research team recently discovered that the female hormones play a role in the differential response of our mouse models to T-cell driven anti-tumor response. 

Our laboratory is equipped with unique mouse models in which the degradation of the essential amino acid, leucine, is blocked at the cytosolic (BCATc) or mitochondrial (BCATm) branched-chain aminotransferase step in T lymphocytes. This blockage allows T lymphocytes to use leucine for activation and growth thus becoming more effective in destroying cancer cells. The next step in our research is to investigate the interplay between the female hormones and the metabolism of leucine in the context of T cell mediated effectiveness in reducing tumor burden alone or in the presence of immunotherapy. A combination of animal tumor studies, molecular, biochemical, bioinformatic and metabolic approaches will be utilized to achieve the goals of this project. Lastly, this project will be in collaboration between Ananieva and Barnes’ laboratories. Barnes’ laboratory is bringing an expertise in animal physiology with emphasis on post-menopausal and diet-induced obese models.

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

Type 2 diabetes (T2D) is a major health problem worldwide. A main pathological feature of T2D is the reduction in function of pancreatic beta cells, leading to reduced production of insulin. We have identified novel mechanisms that can be exploited to promote the secretion of insulin from these cells while protecting their other functions. This project will use a combination of molecular, cellular and biochemical approaches, coupled with studies in animal models and human pancreatic tissues to develop and characterize mechanistically novel therapeutic agents that promote the production of insulin from pancreatic beta cells and test their effects in animal models of T2D. 

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

Physical exercise is fundamental to promoting mental and physical well-being. While the detrimental effects of a sedentary lifestyle on chronic disease risk are well-established, individual responses to and engagement in exercise vary widely. Using unique animal models, our research aims to identify the neural mechanisms driving voluntary exercise behavior, elucidate how physical and psychosocial stress contribute to persistent inactivity and develop methodologies to harness the benefits of exercise and apply them to individuals who are unable to participate in traditional exercise.

Dr. Melissa Meyer, Department of Microbiology and Immunology

Neutrophils develop linearly from progenitors in the bone marrow. During disease, neutrophil production can be amplified and contribute to chronic inflammation. So, it is important to understand new mechanism that control neutrophil development. Recent work by myself and colleagues identified an early neutrophil progenitor that expresses CD71, an iron transporter usually expressed on red blood cell progenitors. This suggests iron metabolism may be important to neutrophil development at the earliest stages. In this project, we will explore the role of iron metabolism in neutrophil development in mouse and human and whether modulating iron metabolism can impact disease progression, particularly in cancer. In this project, you will utilize mouse modeling, human sample analysis, flow cytometry and measurement of metabolic processes.

Dr. Noah Marcus, Dr. Sarah Clayton and Dr. 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.

Dr. Kim Tran and Dr. 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.

Dr. Maria Barnes, Department of Biochemistry and Nutrition

More 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. Kim Tran, Dr. Eric Wauson, Dr. Sarah Clayton and Dr. 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.

Dr. Melissa Meyer, Department of Microbiology and Immunology

Neutrophils are an important component of the immune system and imperative to fighting infections. They can also contribute to chronic inflammation, which supports disease progression, particularly in cancer. Neutrophils typically develop in the bone marrow but are found in the periphery during cancer where neutrophil progenitors are known to promote tumor progression. In this project, we will ask how experiencing the periphery impacts the phenotype and function of those neutrophil progenitors that leave the bone marrow.  To test this, bone marrow neutrophil progenitors will be isolated and placed in the periphery (blood and tumor) of tumor-bearing mice. Later, the transferred progenitors will be collected and measured for changes in phenotype and function. We will further utilize large data sets to understand what signals the progenitors are experiencing in the periphery during cancer, as compared to the bone marrow under healthy conditions.  Finally, we will connect the signals identified in the high dimensional data to the phenotypic and functional changes we identify in neutrophil progenitors experiencing the periphery. In this project, you will learn to work with mouse models of cancer, perform flow cytometry and functional assays and use computational analysis techniques. 

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

Protein kinases regulate many cellular processes and their dysfunction is observed in a variety of human diseases. There are currently approximately 80 FDA-approved kinase inhibitors used in the clinic that target a small number of the known 538 protein kinases encoded by the human genome. Approximately 1/3 of human protein kinases are considered poorly studied and little is known about their substrates or mechanisms of regulation. Thus, there are likely unmet therapeutic opportunities in targeting these understudied kinases. We previously demonstrated that inhibition of an understudied kinase named BMP2-inducible kinase (BMP2K) significantly reduced cardiomyocyte death induced by simulated ischemia. The aim of this project is to determine the mechanism by which BMP2K inhibition prevents cardiomyocyte cell death by using a variety of biochemical, molecular biology and cell biology approaches. The overall goal is to develop novel therapeutic interventions to treat myocardial infarction.