Research Opportunities — PhD

LiLian Yuan, PhD, and Eric Wauson, PhD, Department of Physiology and Pharmacology

Autophagy (and the related process of mitophagy) is a fundamental cellular quality-control pathway that supports healthy aging and overall well-being by clearing damaged proteins and organelles, preserving mitochondrial function, and maintaining tissue resilience across the body. Exercise is one of the most potent physiological activators of these protective programs, yet exercise-induced autophagy has rarely been studied in a coordinated, multi-organ framework, especially in females and across the menopause transition, leaving major gaps in how systemic adaptations are regulated and why functional benefit varies so widely. We will address this by using female rats (young and aged) with sham surgery or ovariectomy (OVX) to test how estrogen loss reshapes exercise-induced autophagy/mitophagy responses across skeletal muscle, heart, and key brain regions that regulate metabolic homeostasis. By linking organ-specific autophagy flux signatures and mitochondrial quality-control markers to functional outcomes (muscle performance, cardiac function, and activity/exercise behavior), this study will define hormone-sensitive “response nodes” and multi-organ biomarker profiles that can be leveraged to optimize exercise-based strategies to preserve health and independence in women during aging.

Francesca Di Sole, PhD, Department of Physiology and Pharmacology

Hypertension is a major cause of cardiovascular disease, affecting nearly half of adults in the United States. Our genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in non-coding regions of the calcineurin homologous protein (CHP) genes that are linked to elevated blood pressure. CHP is a calcium-binding protein that interacts with and regulates the Na⁺/H⁺ exchanger-3 (NHE3), a key determinant of blood pressure through its control of sodium balance and pH homeostasis across multiple organs.

Evidence from our group and others indicates that increased CHP expression enhances NHE3 activity, promoting sodium retention and elevated blood pressure. Although selective NHE3 inhibitors are not yet widely available, NHE3 remains an attractive therapeutic target, making it fundamental to understanding how genetic variation in CHP regulates its activity.

This project explores how genetic variation in the CHP genes contributes to high blood pressure. We are investigating how specific DNA changes affect the regulation of CHP, how this in turn influences the activity of NHE3, and how these mechanisms shape blood pressure control. By combining laboratory studies with analyses of large population datasets, this research aims to deepen our understanding of the genetic basis of hypertension and point to new strategies for future therapies.

Elitsa Ananieva, PhD, and Maria Barnes, PhD, 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 cancer patients, 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 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.

This project will be in collaboration between Ananieva and Barnes’ laboratories. Barnes’ laboratory is bringing expertise in animal physiology with emphasis on post-menopausal and diet-induced obese models.

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

Physical exercise is fundamental to mental and physical well-being. Although the detrimental effects of sedentary behavior on chronic disease risk are well established, individuals vary widely in both their engagement in exercise and their physiological responses to it. Using unique animal models, targeted physiological manipulations, and multi-omics approaches, our research aims to:

1. Identify positive regulators that drive voluntary exercise behavior. We have identified the sex hormone estrogen as a key positive regulator by establishing a causal link between estrogen signaling and voluntary wheel running in females.
2. Identify negative regulators that suppress voluntary exercise behavior. We have shown that psychosocial stress induces persistent physical inactivity and have uncovered striking sex differences in this response.
3. Develop approaches to harness exercise benefits for individuals unable to exercise traditionally. We are developing methodologies to capture and deliver exercise-induced extracellular vesicles.

Eric Wauson, PhD, 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. 

Melissa Meyer, PhD, Department of Microbiology and Immunology

Neutrophils are an important component of the immune system, 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.

Melissa Meyer, PhD, 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 mechanisms 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 mice and humans 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.

Maria Barnes, PhD, 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.

• Maria Barnes, PhD, DMU Department of Biochemistry and Nutrition
• Francesca Di Sole, PhD, DMU Department of Physiology and Pharmacology
• Victor Babich, PhD, 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 a potential interventional approach against hypertension associated with obesity.

• Noah Marcus, PhD, Sarah Clayton, PhD, and Francesca Di Sole, PhD, Department of Physiology and Pharmacology, Des Moines University Medicine and Health Sciences
• James Lang, PhD, Iowa State University
  
• Rodrigo Del Rio, PhD, 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 sleep apnea. Current projects in the lab are focused on determining the autonomic, hemodynamic and biochemical mechanisms by which sleep apnea 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 sleep apnea and inform condition-appropriate treatment for PCOS patients with sleep apnea.

Vanja Duric, PhD, and Francesca Di Sole, PhD, 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 homeostasis. Clinical depression, anxiety and other psychiatric symptoms are commonly present in patients with different chronic systemic diseases such as chronic pain and chronic 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 biochemical and pharmacological approaches in combination with stress animal models, 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 of mental health comorbidities associated with different systemic illnesses such as acute kidney injury and chronic kidney disease.