Biotechnology

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

William Montfort, PhD, determines the atomic structures of proteins and seeks to understand how protein structure gives rise to protein function – both in vitro and in living cells. At their heart, the problems have a fundamental structure-function question, but also address questions of importance to human health. Approaches include X-ray crystallography, rapid kinetic measurements, spectroscopy, theory, protein expression, drug discovery, molecular genetics and related techniques.Dr. Montfort is particularly interested in nitric oxide signaling mechanisms. Nitric oxide (NO) is a small reactive molecule produced by all higher organisms for the regulation of an immensely varied physiology, including blood pressure regulation, memory formation, tissue development and programmed cell death. He is interested in two NO signaling mechanisms: binding of NO to heme and the nitrosylation (nitrosation) of cysteines. NO, produced by NO synthase, binds to soluble guanylate cyclase (sGC) at a ferrous heme center, either in the same cell or in nearby cells. Binding leads to conformational changes in heme and protein, and to induction of the protein’s catalytic function and the production cGMP. NO can also react with cysteine residues in proteins, giving rise to S-nitroso (SNO) groups that can alter protein function. He continues to study the mechanistic details surrounding cGMP and SNO production, and the signaling consequences of their formation.For reversible Fe-NO chemistry, Dr. Montfort is studying soluble guanylate cyclase and the nitrophorins, a family of NO transport proteins from blood-sucking insects. Our crystal structures of nitrophorin 4 extend to resolutions beyond 0.9 angstroms, allowing us to view hydrogens, multiple residue conformations and subtle changes in heme deformation. For reversible SNO chemistry, he is studying thioredoxin, glutathione S-nitroso reductase (GSNOR) and also sGC. For regulation in the cell, Dr. Montfort and his group have constructed a model cell system based on a human fibrosarcoma called HT-1080, where sGC, NO synthase, thioredoxin and GSNOR can be manipulated in a functional cellular environment. With these tools, they are exploring the molecular details of NO signaling and whole-cell physiology, and undertaking a program of drug discovery for NO-dependent diseases. Keywords: Structural Biology, Drug Discovery, Cancer, Cardiovascular Disease

Raina M Maier, PhD, is a Professor of Environmental Microbiology in the Department of Soil, Water and Environmental Science and Director of the University of Arizona NIEHS Superfund Research Program. She also serves as Director of the University of Arizona Center for Environmentally Sustainable Mining and as Deputy Director of the TRIF Water Sustainability Program. Dr. Maier is internationally known for her work on microbial surfactants (biosurfactants) including discovery of a new class of biosurfactants and of novel applications for these unique materials in remediation and green technologies. She is also recognized for her work on the relationships between microbial diversity and ecosystem function in oligotrophic environments such as carbonate caves, the Atacama desert, and mine tailings. Dr. Maier has published over 100 original research papers, authored 23 book chapters, and holds a patent on the use of biosurfactants to control zoosporic plant pathogens. She is the lead author on the textbook “Environmental Microbiology” currently in its second edition.Dr. Maier emphasizes a multidisciplinary approach to her work and has served as PI or co-PI on several large granting efforts including the UA NIEHS Superfund Research Program, the UA NSF Kartchner Caverns Microbial Observatory, and the UA NSF Collaborative Research in Chemistry grant on biosurfactants.

Dr. Madhavan M.D., PhD, is an Assistant Professor of Neurology at the University of Arizona. She is also a member of the Arizona Cancer Center and the Evelyn F. McKnight Brain Institute, and is affiliated with the Neuroscience, Physiology and Molecular, Cellular Biology graduate programs at UA. Dr. Madhavan’s research centers on stem cells and neurological diseases. The ultimate goal of the work is to devise brain repair strategies for neural disorder using stem cells, and other alternate approaches. Currently, her lab is focused on Parkinson’s Disease, and is engaged in three main endeavors: (1) Understanding the therapeutic potential of stem cells in the context of aging, (2) Creating patient-specific induced pluripotent stem cells to study the etiology of Parkinson’s Disease, and (3) Testing the therapeutic feasibility of various types of adult stem cells in preclinical Parkinson’s Disease models. These projects are united by a common goal, which is to investigate core problems hindering the development of effective stem cell-based therapies for Parkinson’s Disease. In addition, the work represents a novel path of research for not only Parkinson’s Disease therapy, but has broad implications for developing treatments for several other age-related neurodegenerative disorders. Visit the Madhavan Lab website to learn more.

Public Relevance Statement: Can you imagine having a mouthful of canker sores and cavities? Thousands of head and neck cancer patients suffer these consequences from radiation treatment. The Limesand lab works to prevent these side effects thereby improving patients' quality of life. Clinical Relevance: Radiation therapy for head and neck cancer causes adverse secondary side effects in the normal salivary gland including xerostomia, oral mucositis, malnutrition, and increase oral infections. Although improvements have been made in targeting radiation treatment to the tumor, the salivary glands are often in close proximity to the treatment site. The significant destruction of the oral cavity following radiation therapy results in diminished quality of life and in some cases interruptions in cancer treatment schedules. Research Interests: My research program has its foundation in radiation-induced gland dysfunction; mechanisms of damage, clinical prevention measures, and restoration therapies. Evidence suggests that salivary acinar function is compromised due to apoptosis induced by these treatments and temporary suppression of apoptotic events in salivary glands would have significant benefits to oral health. We utilize a number of techniques in my laboratory including: genetically engineered mouse models, real-time RT/PCR, immunoblotting, immunohistochemistry, primary cultures, siRNA transfections, irradiation, and procedures to quantitate salivary gland physiology. Current project areas: 1. Radiation-induced apoptosis 2. Mechanisms of preserving salivary gland function 3. Identifying the radiosensitivity of salivary gland progenitor cells 4. Restoration of salivary gland function 5. Role of autophagy in radiation-induced loss of function

Yann C. Klimentidis, PhD, is an Associate Professor in the Department of Epidemiology and Biostatistics in the Mel and Enid Zuckerman College of Public Health at the University of Arizona. His research centers on improving our understanding of the links between genetic variation, lifestyle factors, metabolic disease, and health disparities. In the past, he has used measures of genetic admixture and genomic tests of natural selection to understand the genetic basis of population differences in disease susceptibility. His most recent work examines the use various statistical approaches for the analysis of high-dimensional genetic data for improving prediction of genetic susceptibility to type-2 diabetes. In addition, his work examines gene-by-lifestyle interactions in type-2 diabetes, as well as understanding the causal links between metabolic traits such as dyslipidemia and type-2 diabetes. Keywords: Genetics, epidemiology, Cardiometabolic disease, Physical activity

Walter T. Klimecki, DVM, PhD, is an Associate Professor in the Department of Pharmacology and Toxicology in the College of Pharmacy at the University of Arizona. Dr. Klimecki holds joint appointments in the College of Medicine, the College of Public Health, and the Arizona Respiratory Center. He is a Full Member of the Southwest Environmental Health Sciences Center (SWEHSC) where, together with BIO5 director Martinez and BIO5 Statistics Consulting Service director Billheimer, he leads the Integrative Health Sciences (IHS) Center at SWEHSC. The IHS is a translational research support core at SWEHSC, focused on lowering the “activation energy” for translational research.Dr. Klimecki’s research focuses on the toxicology of metals in the environment, an issue particularly relevant in our mining-intensive state. His research work has encompassed a wide range of experimental approaches, from epidemiological studies of arsenic-exposed human populations, to laboratory models including cell culture and rodents. Using cutting edge genetics tools, Dr. Klimecki’s group recently published the first report of an association between human ancestry and response to environmental toxicants. In this provocative work, his group found that individuals whose genomes were comprised of DNA with its origins in the indigenous American populations processed ingested arsenic in a less harmful manner than did individuals whose genomes had their origins in Europe. Using laboratory models his group made ground-breaking discoveries of the impact of arsenic exposure on a process known as autophagy, in which cells digest parts of their own machinery in a sort of “cash for clunkers” arrangement. The ability of arsenic to perturb this process is only now being appreciated by the toxicology community, thanks to the work of the Klimecki Lab. Dr. Klimecki was recently elected as a Vice President-elect to the Metals Specialty Section of the Society of Toxicology, the preeminent scientific toxicology organization in the world. Dr. Klimecki’s research is highly collaborative: his grants and publications have included many BIO5 members, including BIO5 director Fernando Martinez, and BIO5 members Donata Vercelli, Dean Billheimer, and Marilyn Halonen.

Minkyu Kim, Ph.D., is an Assistant Professor in the Department of Materials Science and Engineering and the Department of Biomedical Engineering at the University of Arizona. He received a M.S. (2006) in Biomedical Engineering and a Ph.D. (2011) in Mechanical engineering and Materials Science at Duke University. During his Ph.D., he worked in the Single-Molecule Force Spectroscopy group led by Prof. Marszalek. He was a postdoc at MIT from 2012 to 2016, and worked in the Bioinspired and Biofunctional Polymers group led by Prof. Olsen. Dr. Kim’s research is focused on the design and development of biopolymer-based functional materials for targeted applications in healthcare and for national defense. Based on his diverse research experiences in the areas of biopolymer nanomechanics, polymer physics and self-assembly, biomolecular engineering and soft materials, his group is currently developing (a) mechanically responsive soft materials that mimic reversible deformability of red blood cell and that can be utilized as targeted drug delivery vehicles for the early treatment of atherosclerosis and (b) nuclear membrane inspired biopolymer materials that selectively filter and neutralize a broad range of bacteria, fungi and viruses for pharmaceutical, food safety, water decontamination and defense applications. In addition to biomaterial development to mitigate atherosclerosis and infectious diseases, Dr. Kim is also interested in addressing how bioinspired design and biosynthesis can be used for the preparation of novel functional materials, how the nanomechanics of folded biopolymers and artificially engineered hyperbranched biopolymer structures can be translated into the mechanics of macromolecular materials that provide new insight into polymer science, and how protein sequences can control parameters that regulate the functional properties of polymeric materials. Lab Website: http://kim.lab.arizona.edu

Laurence Hurley, PhD, embraces an overall objective to design and develop novel antitumor agents that will extend the productive lives of patients who have cancer. His research program in medicinal chemistry depends upon a structure-based approach to drug design that is intertwined with a clinical oncology program in cancer therapeutics directed by Professor Daniel Von Hoff at TGen at the Mayo Clinic in Scottsdale. Dr. Hurley directs a research group that consists of a team of graduate and postdoctoral students with expertise in structural and synthetic chemistry working alongside students in biochemistry and molecular biology. NMR and in vivo evaluations of novel agents are carried out in collaboration with other research groups in the Arizona Cancer Center. At present, they have a number of different groups of compounds that target a variety of intracellular receptors. These receptors include: (1) transcriptional regulatory elements, (2) those involved in cell signaling pathways, and (3) protein-DNA complexes, including transcriptional factor-DNA complexes.In close collaboration with Dr. Gary Flynn in Medicinal Chemistry, he has an ongoing program to target a number of important kinases, including aurora kinases A and B, p38, and B-raf. These studies involve structure-based approaches as well as virtual screening. Molecular modeling and synthetic medicinal chemistry are important tools.The protein–DNA complexes involved in transcriptional activation of promoter complexes using secondary DNA structures are also targets for drug design.

Christopher Hulme, PhD, focuses on small molecule drug design and developing enabling chemical methodologies to expedite the drug discovery process. Target families of particular current interest for the group are kinases, protein-protein interactions and emerging DNA receptors for indications in oncology. Such efforts are highly collaborative in nature and students will be exposed to the full array of design hurdles involved in progressing molecules along the value chain to clinical evaluation. These efforts will be aided by the group’s interest in both microwave assisted organic synthesis (MAOS) and flow chemistry. Both technologies enable ‘High-throughput Medicinal Chemistry’ (HTMC) and will be supported by similar High-throughput Purification capabilities.The group also has a long standing interest in the development of new reactions that produce biologically relevant molecules in an efficient manner. Front loading screening collections with molecules possessing high ‘iterative efficiency potential’ is critical for expediting the drug discovery process. The discovery of such tools that perturb cellular systems is of high value to the scientific community and may be facilitated by rapid forays into MCR space that can produce a multitude of novel scaffolds with appropriate decoration for evaluation with a variety of different screening paradigms.Novel hypervalent iodine mediated C-H activation methodologies is also an active area of interest. Probing the scope of the transformation below and investigating applications toward the synthesis of new peptidomimetics will be an additional pursuit in the Hulme group.