Chemistry

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.

My research is focused on developing novel optical microscopy technologies and improving patient care using these technologies. My research area includes (1) low-cost smartphone in vivo microscopy, (2) high-speed comprehensive in vivo endomicroscopy, and (3) ultraminiature endomicroscopy. (1) Low-cost smartphone in vivo microscopy: I am currently leading a NIH-sponsored research project for developing smartphone confocal microscope and diagnosing Kaposi's sarcoma in Uganda with the smartphone confocal microscope. I will further advance the smartphone microscopy technology and address other applications, including diagnosis of cervical and oral cancers in low-resource settings, large-population screening of skin cancers in the US, and aiding science and medical educations. (2) High-speed comprehensive in vivo endomicroscopy: I have previously developed a high-speed confocal microscopy system and endoscopic imaging catheters and acquired largest in vivo confocal images of human organ reported. At the UA, I plan to further advance the technology by i) increasing the imaging speed by orders of magnitude and ii) incorporating fluorescence imaging modality. (3) Ultraminiature endomicroscopy: In my previous research, I have developed miniature endoscopic catheters that can visualize internal organs in vivo through a needle-sized device. At the UA, I will develop microscopic imaging catheter with a extremely small diameter and utilize it for guiding cancer diagnosis and treatment.

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.

Ultrafast Electron Microscopy is a pivotal tool for imaging the atomic motion in real time and space. The temporal resolution, limited to a few hundreds of femtoseconds (one quadrillionth of a second) permits recording movies of only the relatively massive atomic motion. Imaging of microscopic motions outside the atomic nucleus in the real-time requires a significant enhancement in the temporal resolution. My research program aims to obtain the attosecond (one quintillionth of a second) temporal resolution in electron microscopy and establish the “Attomicroscopy” —the fastest camera ever known—which takes the field of ultrafast imaging to the next level. Attomicroscopy provides a real-time access to all microscopic motions outside the atomic core and radically change our insight into the workings of the microcosm. We will use the Attomicroscopy to image the electron motion in biochemical molecules such as amino acids, DNA, protein…. etc. Attosecond imaging and controlling of the electron motion at the atomic scale will open exciting new ground and prospects in multiple fields of basic science, biological applications, and information technology.

Despite many therapeutic successes, cancer remains a major cause of mortality in the US. Natural products (NPs) represent the best source and inspiration for the discovery of drugs and molecular targets. Our aim is to discover effective and non-toxic NP-based anticancer drugs. Working with NCI we have recently discovered a class of plant-derived NPs useful in cancer immunotherapy. The main focus of our current research is to utilize medicinal chemistry approach to obtain their analogues for preclinical evaluation. Leslie Gunatilaka is Professor at the School of Natural Resources and the Environment and Director of the Natural Products Center. He is also Adjunct Professor of Department of Nutritional Sciences, and a member of the Arizona Cancer Center. He is a member of several professional societies, editorial boards, and pharmaceutical company advisory groups. He is a Fellow of the Academy of Sciences for the Developing World (TWAS), Italy, and the National Academy of Sciences, Sri Lanka. Dr. Gunatilaka has over 200 peer-reviewed publications and book chapters and over 150 communications in natural product science to his credit. He is the recipient of the Sri Lankan Presidents’ gold medal for “creating a center of excellence in natural products research at the University of Peradeniya, Sri Lanka” (1987), CaPCURE award for “dedication to ending prostate cancer as a risk for all men and their families” (2000), Research Faculty of the Year Award of the UA College of Agriculture and Life Sciences (2003), the UA Asian American Faculty, Staff and Alumni Association Outstanding Faculty Award (2005), and the UA Leading Edge Researcher Award for Innovative Research (2012). He has delivered over 100 invited lectures worldwide and was the Chief Guest and Plenary Lecturer at the International Herbal Medicine Conference held in Sri Lanka (2005), and the Keynote Speaker and the Guest of Honor at Chemtech-2007, an International Conference organized by the Institute of Chemistry, Ceylon. His current research interests include discovery, identification of protein targets, and structure-activity relationship (SAR) studies of natural product-based drugs to treat cancer, neurodegenerative, and other diseases from plants, and plant- and lichen-associated microorganisms, maximization of chemistry diversity and production of microbial and plant secondary metabolites, and scientific investigation of medicinal plants and herbal supplements. Keywords: Natural Product-Based Drug Discovery, Medicinal Chemistry, Cancer Immunotherapeutic Agents

Hendrikus Granzier, PhD, studies the mechanisms whereby the giant filamentous protein titin (the largest protein known) influence muscle structure and function. His lab has shown that titin functions as a molecular spring that mediates acute responses to changing pathophysiological states of the heart. They also study the role of titin in cardiac disease, using mouse models with specific modifications in the titin gene, including deciphering the mechanisms that are responsible for gender differences in diastolic dysfunction. An additional focus of Dr. Granzier’s lab is on nebulin, a major muscle protein that causes a severe skeletal muscle disease in humans. Based on previous work, they hypothesize that nebulin is a determinant of calcium sensitivity of contractile force. To test this and other concepts, he uses a nebulin knockout approach in the mouse. Research is multi-faceted and uses cutting-edge techniques at levels ranging across the single molecule, single cell, muscle, and the intact heart. His research group is diverse and has brought together individuals from several continents with expertise ranging from physics and chemistry to cell biology and physiology.

I am a senior research scientist and oversees medicinal chemistry research at BIO5 Institute's drug discovery initiative. I oversee group of medicinal chemistry involved in the development of small molecule therapeutics for idiopathic pulmonary fibrosis (IPF), neuropathic pain, acute lung injury and cancer. I am co-founder of Reglagene and Regulonix - two biotech companies with startup technology from the University of Arizona. I have 15 years' experience in medicinal chemistry with expertise in translational drug development. I am also a co-inventor of small molecules targeting hTERT and MYC for the treatment of glioblastoma, melanoma, lymphomas and prostate cancer. Our work in the area of neuropathic pain has led to successful funding from Tech Launch Arizona and will result in STTR funding from NIH.

Janet L. Funk, MD, FACP, is a Professor of Medicine at the University of Arizona College of Medicine. Dr. Funk leads a federally-funded research team that is focused on identifying new treatments for chronic diseases that have strong inflammatory components, including metabolic bone diseases, such as arthritis, bone tumors and osteoporosis, and cardiovascular diseases, including diabetes. Recent studies have focused on the use of medicinal plants that have historically been used to treat inflammatory conditions, such as arthritis. By understanding whether and how these plants work in blocking inflammatory pathways in the body, we are striving to harness the power of nature and the wisdom of our ancestors to indentify new treatments for diseases that are common in our modern society. Discoveries we have made at the lab bench have allowed us to move forward into the clinics, building upon the old to discover the new.

Joan Curry, PhD, stands in the field of research related to interfacial chemistry, which is a focus within physical chemistry. Within interfacial chemistry, she focuses on chemistry of molecules at the interfaces where solids and liquids come together. The term solid here includes mineral and bacterial surfaces found in soils and sediments, metal and oxide machine surfaces and cell surfaces found in the human body. Molecules can be water and ions that bathe soil surfaces, organics that lubricate machine parts and large biomacromolecules, such as proteins and lipopolysaccharides, attached to cells that mediate cell adhesion. Her specific interests are: 1) determining the effect of confinement on liquids in general and lubricants in particular and 2) characterizing the adhesive properties of cell surface biomacromolecules. The primary goal of this work is to understand how biomacromolecules that cover cell surfaces influence the interaction and adhesion of cells with other cells and with solid surfaces. Cells can be either bacteria or human cells. It is important to understand bacterial adhesion because it is the first step in biofilm formation, which has numerous undesirable consequences ranging from heat exchanger fouling to medical implant infections. Currently, very little is known about how bacterial surface biomacromolecules mediate adhesion and therefore it is still not possible to control or manipulate the process. Human cell adhesion is also mediated by biomacromolecules, in particular proteins that bind to one another through specific lock and key mechanisms. The structure of many cell adhesion proteins is well known but their function is still poorly understood. In collaboration with Ronald Heimark (Surgery), Dr. Curry is working to understand how heavy metals such as cadmium affect the binding of cell adhesion proteins called cadherins. This work will help scientists understand better how heavy metals may lead to birth defects and in adults could accelerate cardiovascular disease. This work is experimental and involves direct force measurements between biomembrane covered mica surfaces with the Surface Forces Apparatus (SFA). With the SFA it is possible to measure the magnitude and distance dependence of molecular forces acting between two flat surfaces with angstrom and nanonewton resolution.

Erica Corral, PhD, essentially dives into three primary areas of research. Her first research area focuses on processing ultra-high temperature ceramic (UHTC) composites and coatings for use as advanced thermal protection systems and to provide oxidation protection of carbon-carbon composites. Secondly, she focuses on developing bulk multifunctional high-temperature ceramic nanocomposites reinforced with single-walled carbon nanotubes for enhanced toughness in ceramics that also have tailored electrical and thermal properties. Last but not least, Dr. Corral also focuses on developing nanocomposite compositions of iron oxide and zirconia for use as hydrogen generation materials. Recent postdoctoral research also focused on investigating the thermomechanical properties of UHTCs, and engineering mechanical and chemical properties of glass-composites for use as reliable seals in solid oxide fuel cells, and ceramic powder processing of magnesium oxide and electrolyte powder for use in thermal batteries. As a graduate student at Rice University, Dr. Corral was an NSF-Alliance for Graduate Education and the Professoriate (AGEP) Fellow, and pioneered the first SWNT-reinforced silicon nitride nanocomposites with multifunctional properties.