Health

Timothy Secomb, PhD, studies the microcirculation, a network of extremely small blood vessels that supply oxygen and nutrients to all parts of our tissues. The focus of work in his research group is the use of mathematical and computational approaches to study blood flow and mass transport in the microcirculation. Working in collaboration with experimentalists, the aim is to understand quantitatively the processes involved. Dr. Secomb examines the relationship between red blood cell mechanics and flow resistance in microvessels. Theoretical predictions agree well with observations in glass tubes, but resistance is higher living tissue. The major cause is the presence of a relatively thick macromolecular lining (endothelial surface layer) on the walls of microvessels. He also simulates oxygen exchange between networks of microvessels and surrounding tissues in skeletal muscle and tumors. In skeletal muscle, oxygen can be exchanged diffusively between arterioles and capillaries, and Dr. Secomb’s lab is studying the determinants of maximal oxygen consumption. In tumors, the relationship between network structure and occurrence of local hypoxic (radiation-resistant) regions is a source of curiosity. They are analyzing the delivery of chemotherapeutic drugs in tumor tissues, and developing improved models to describe the responses of tumor cells to chemotherapy and radiation. Models for the structural responses of microvessels to functional demands are being developed. Maintenance of a stable, functionally adequate distribution of vessel diameters can be achieved if each vessel responds to changes in wall shear stress, intravascular pressure and local metabolic conditions, and if mechanisms exist for information transfer upstream and downstream along flow pathways. Models for the active regulation of blood flow by changes in vascular tone are also being developed, taking into account vascular responses to wall shear stress, pressure and local metabolic state, and including effects of conducted responses along vessel walls. Another project in the group is the development of computer simulations for the dynamics of the left ventricle that can be run in real time and provide a tool for analysis of data derived from ultrasound echocardiography images.

My laboratory investigates the normal biology of the Epidermal Growth Factor Receptor (EGFR, and its family members, HER2 and ErbB3), as well as their role in transformation and metastasis. These oncogenes are a family of transmembrane tyrosine kinases that drive a wide-variety of cancers including HER2 positive and triple negative breast cancer, squamous cell lung cancer and glioblastoma. Our work focuses on kinase-independent activities of these receptors (such as modulation of calcium signaling and functions as transcriptional co-factors) and how the receptors are mis-regulated during cancer progression (by a loss of lysosomal degradation). These studies include investigations into receptor trafficking, nuclear translocation and protein-protein interactions that are unique to cancer survival and metastasis. We are currently focused on understanding how EGFR enters the retrotranslocation pathway that allows for it to traffic to the nucleus and directly affect gene transcription, as well as understanding how these events drive migration and survival. Based on these studies, we have developed peptide-based therapeutics for cancer that block protein-protein interactions that promote EGFR retrotranslocation. We are developing these peptide-based therapeutics for clinical applications through peptide stability studies including hydrocarbon stapling and mutational analyses. To promote the clinical translation of these discoveries, the biotech start-up company Arizona Cancer Therapeutics was founded in my lab at the Arizona Cancer Center. We are currently performing toxicity testing of our compounds with the goal of applying for approval from the FDA for clinical trials. These studies have been accomplished through the hard work and dedication of the over 50 undergraduate students, 2 MS and 11 PhD students who have studied in my lab since 2002.

Monica Schmidt is an Associate Professor in the School of Plant Sciences in the College of Agricultural and Life Sciences at the University of Arizona. Dr. Schmidt’s research interests are in both functional foods and functional genomics. Her research aims at applying molecular biology and genetic techniques to help alleviate current major agricultural problems. As soybean is a global commodity, much of her research focuses on soybean seed traits. Current research is investigating cellular mechanisms to strengthen the metabolic engineering efforts to fortify crops with nutraceutical carotenoids. Since soybean oil is a large component of the American diet, Dr. Schmidt is also investigating means to engineer a more healthy oil composition. Other functional food projects aim at the suppression of deleterious compounds in crops, such as toxins produced from contaminating fungus, in maize and peanuts. She uses techniques of plant biotechnology in over a dozen crops to investigate gene function, at a cellular and entire plant level. Dr. Schmidt has worked with both domestic and international collaborators on value-added traits in seeds of legumes for over a decade and is one of the few academic laboratories that can routinely transform soybean. She has been involved with a number of innovations in tissue culture / transformation techniques (for example, maturation media for soybean, novel gene expression cassette system) and her research on seed manipulation has resulted in a start-up company and patents. Keywords: plant biotechnology, functional foods, soybean, maize

Dr. Monika Schmelz is a Assistant Professor of Pathology and Member of the University of Arizona Lymphoma Consortium. Dr. Schmelz pursuing research on mechanisms for immune escape in aggressive lymphoma with poor survival rates. Dr. Schmelz received a 2 year award (2013-2015) from The Hope Foundation to study how tumor cells escape immunosurveillance, which is a hallmark of cancer, in aggressive diffuse large B-cell lymphoma (DLBCL) with poor patient outcome, and how immunosurveillance can be manipulated for therapeutic purposes. ( see also link: http://pathology.arizona.edu/news/dr-monika-schmelz-recipient-2013-swog-development-award). Dr. Schmelz also is pursuing biorepository science. She received a multi-million dollar award for hosting the Biorepository for a NCI funded clinical trial. ANCHOR is a multi-site phase III clinical trial entitled “Topical or Ablative Treatment in Preventing Anal Cancer in Patients with HIV and Anal High-Grade Squamous Intraepithelial Lesions”. 17,385 participants will be screened to identify and to enroll 5,058 eligible participants. An estimated 314,535 biospecimens over the duration of the clinical trial (8 years) will be collected and sent to Dr. Schmelz's lab. The biorepository is an extremely important factor for the outcome of this clinical trial, since correlative translational studies on biomarkers for early detection of anal cancer development in these specimens are planned by the NCI. Keywords: Cancer, Diffuse Large B-Cell Lymphoma (DLBCL), Therapeutic Biomarkers

Dr. Schlenke's research program uses fruit flies in the genus Drosophila to understand the evolutionary genetics of host-parasite interactions. For example, his lab has developed several species of parasitic wasps, which are readily observed infecting Drosophila in nature and can be very specialized to particular host species, as model parasites. These wasps lay single eggs in Drosophila larvae and, once hatched, consume flies from the inside out. Flies mount cellular and behavioral defense responses against wasps, but wasps have adaptations for finding host fly larvae, suppressing host cellular immunity, and manipulating host behavior. The Schlenke lab uses a variety of "omics" tools to understand the molecular genetics of fly cellular immunity and wasp virulence, as well as patterns of host immunity and pathogen virulence coevolution across fly and wasp phylogenies. The Schlenke lab also studies the genetics and neurobiology of behaviors that flies use to avoid being infected by the wasps and to cure themselves once they are infected, including various self-medication behaviors.

Our laboratory is both experimental and computational. We use next-generation sequencing technologies to measure genome-wide molecular phenotypes. By leveraging the interconnected relationships between DNA sequence, transcription factor binding, chromatin modification, and gene expression, we study how cells achieve context-appropriate expression patterns and signal responsiveness. Lab Website: www.romanoskilab.com Keywords: Genetics, Genomics, Vascular Biology, Bioinformatics

Donato Romagnolo, MSc, PhD, has served as a member of study sections for the National Institutes of Health, the U.S. Department of Defense, the Susan G. Komen Breast Cancer Foundation, and as a scientific reviewer for nutritional, cancer, and pharmacology and toxicology scientific journals. Dr. Romagnolo is a member of the Training Grant in Cancer Biology at the University of Arizona. Dr. Romagnolo's research focuses on: 1) mechanisms of epigenetic silencing of tumor suppressor genes by environmental and dietary xenobiotics, and 2) role of dietary bioactive food components in the etiology and prevention of cancer and inflammation. For the last 14 years, Dr. Romagnolo's research has been funded by grants from the National Institutes of Health, the U.S. Army Department of Defense, the Susan G. Komen for the Cure and the Arizona Biomedical Research Commission.Some of his research reveals humans are exposed to a complex mixture of ligands of the aromatic hydrocarbon receptor (AhR). Prototypical AhR agonists include the polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P), and the dioxin-like compound 2,3,7,8 tetrachlorodibenzene(p)dioxin (TCDD). Increased incidence of breast cancer is documented in human populations of industrialized areas where high levels of dioxins are found in the air, soil, drinking water, and cow milk. Unlike PAH, TCDD is not metabolized and it promotes tumor development. Population studies reported the presence of TCDD in breast milk, suggesting this agent may accumulate in breast tissue and be a potential risk factor in mammary neoplasia. The in-utero activation of the AhR with TCDD increased the susceptibility to mammary carcinogens in rat female offspring. The activation of the AhR pathway may increase the susceptibility to breast cancer through epigenetic silencing of tumor suppressor genes, including p16 and p53, while inducing transcription of the proinflammatory COX-2 gene.

Ian Robey, PhD, is a Research Assistant Professor with the Department of Medicine, University of Arizona, and a Full Investigator at the Arizona Cancer Center. Dr. Robey is a new investigator studying the role of pH in tumor behavior. He is interested in the mechanisms driving acid-mediated invasion and metastases and how pH modulation can be used for therapeutic purposes in cancer treatment.Dr. Robey is published in over 20 research articles ranging in immunology and cancer biology. He regularly presents his research at national meetings and conferences. He is a lecturer for the introductory biology course for Biomedical Engineering and serves as a committee member for graduate student comprehensive examinations. He is a mentor for Molecular and Cellular Biology student projects. He has been a regular attending and voting IRB member since 2008. He is a regular peer reviewer of grant proposals and manuscripts. Dr. Robey’s current research is focused on investigating the mechanisms of systemic alkalinization in tumor bearing mice to inhibit the spread of metastases. The objective of my project is to advance the preclinical findings on the effects of tumor alkalinization to promote the application of eventual clinical trials with the expectation of establishing a research program bridging integrative medicine and diagnosis/ therapy driven non-invasive imaging methodologies.

CURRENT AND FUTURE RESEARCH PLANS Renquist lab research can be broken into 4 foci that target the pathophysiologies of obesity (insulin resistance, hypertension, and cancer) or aim to better understand energy balance (food intake and energy expenditure) to combat the obesity epidemic. 1) Metabolic Syndrome: Excess hepatic lipid accumulation, common in obesity, is directly related to the incidence and severity of Type II Diabetes Mellitus and hypertension. Hepatic lipid accumulation depolarizes the hepatocyte. To understand the role of hepatocyte membrane potential in mediating the pathophysiologies of obesity, we use tissue specific knockout, pharmacological, and mouse models with adenovirus induced ion channel expression. Through this research we have found that obesity changes hepatocyte neurotransmitter release to affect activity of the hepatic vagal afferent nerve. This research has been supported by competitive grants from the Arizona Biomedical Research Commission and The American Heart Association. Primary hypothesis: Hepatic membrane potential is communicated through the peripheral nervous system to affect serum glucoregulatory hormones, peripheral tissue glucose uptake, and blood pressure. 2) Targeted cell ablation. In two grants funded by Found Animals Foundation, we have focused on inducing permanent sterility by selectively delivering a GnRH targeted toxin to GnRH receptive gonadotropes (A strategy developed by Terry Nett, CSU). The cancer field is demanding delivery systems that improve ligand or antibody directed therapeutics. Many cancers (e.g. breast, ovarian, melanoma, pancreatic, and colorectal) express GnRH receptors. Thus, effective GnRH-targeted toxins can also be directed to target cancer. Two issues have limited the application of GnRH targeted toxins. First, the potential for effects in ‘non-targeted’ GnRH expressing cells. Second, the endosomal sequestration of internalized toxins. By separately targeting an endosome disrupter with one G-protein coupled receptor (GPCR) ligand and the toxin with another GPCR ligand, we eliminate both limitations. By using this modification of the delivery system to maximize endosome escape, we have increased in vitro efficacy more than 1,000,000,000 times. This improvement in efficacy helped our research team to secure a DoD grant aimed applying this strategy to prostate cancer. Importantly, GnRH targeted doxorubicin has recently been approved by the FDA for treatment of cancer. We fully expect that our targeted endosome disrupters would enhance the efficacy of this FDA approved treatment while improving specificity and decreasing the potential for side effects. Primary hypothesis: Optimizing GnRH-toxin conjugates to enhance endosome escape will allow for selective ablation of target cells encouraging the development of improved ligand directed chemotherapeutics and an injectable sterilant 3) Control of food intake and milk production. Understanding the mechanisms that regulate food intake under differing environmental conditions provides opportunities to pharmacologically manipulate phagic drive to treat obesity. Heat stress depresses food intake dependent on histamine signaling. My lab aims to understand how the neuroendocrine/endocrine suppression of visceral blood flow, a physiological adaptation to encourage heat loss by increasing cutaneous blood flow, depresses phagic drive. This USDA NIFA funded project is focused on the dairy cow as our target species, but we employ mouse models and see this as an opportunity to better understand the control of food intake. We use mice that lack histamine receptors to focus on the role of central nervous system histamine signaling in the control of blood flow to the digestive tract and mammary gland. Therapeutics aimed at suppressing visceral blood flow may have application in addressing the obesity epidemic. Primary hypothesis: A decrease in blood flow to the digestive tract and mammary gland is responsible for a decrease in food intake and milk production common to heat stress. 4) Energy Expenditure. I developed an assay to measure the metabolic rate of embryonic zebrafish for application in drug and gene discovery. Since joining the University of Arizona, I have secured funding from USDA Western Regional Aquaculture Center and USDA NIFA funding to apply this assay to identify fish that are genetically superior for growth. We further showed that by measuring the metabolic rate of skeletal muscle biopsies from adult fish, we could identify the fish that were more feed efficient. Skeletal muscle biopsies from adult feed efficient fish were less metabolically active. Recently, we have initiated studies using tissue biopsies from homeothermic mice. This research will allow us to assess the tissue specific response to physiological perturbations (e.g. exercise, diet, obesity, fasting). Since insulin and leptin both increase energy expenditure, we expect that assays performed in tissue explant from homeotherms may allow for screening of insulin and leptin sensitizers in a more physiologically relevant model. We further propose this this assay could be a tool to assess insulin or leptin resistance and drug response in patient biopsies. Primary hypothesis: This assay designed for high throughput metabolic rate determination may be applied to improve growth and feed efficiency in production animals, improve drug development and gene discovery in biomedical models, or personalize medicine for patients. Keywords: Obesity, Metabolic Syndrome, Cancer

Sadhana Ravishankar, PhD, focuses on the stress response in foodborne pathogenic bacteria, including methods of pathogen control and natural antimicrobials. In the lab, Dr. Ravishankar attempts to control foodborne pathogenic bacteria including antibiotic resistant strains using various technologies and multiple hurdle approaches. Natural antimicrobials and their applications in various foods, antimicrobial and anti-oxidative activities of plant compounds also interest her. Bacterial attachment, biofilm formation and their control along with stress tolerance responses of foodborne pathogenic bacteria, and mechanisms of stress response in bacteria are some other subjects of research for Dr. Ravishankar’s lab.