Genetics

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

Rebecca Mosher, PhD, studies how epigenetic information is passed from parent to offspring. Epigenetic information refers to signals laid on top of DNA sequence that affect how and when genes are turned on. Examples of epigenetic signals include chemical modifications of DNA, packaging of DNA around proteins, or the position of DNA in the nucleus. Beginning with Mendel’s observations of pea plants, we have developed a robust understanding of how genetic information in the form of DNA is passed from parent to offspring, but we are only beginning to comprehend how and when epigenetic information is passed from generation to generation. Some epigenetic marks are erased and re-established during reproduction, while others are inherited for many generations. Using plants as models, the Mosher lab studies how tiny RNA molecules place and erase epigenetic marks during reproduction and how the epigenetic marks from the maternal and paternal genomes interact after fertilization.

My laboratory studies neurogenetic mechanisms which underlie normal and abnormal motor speech using the zebra finch songbird. My particular focus is to investigate molecular and cellular pathways altered by speech disorders associated with natural aging and neurological diseases such as Parkinson’s Disease. To carry out these investigations, we use a combination of behavioral, genetic, biochemical and electrophysiological approaches that enable us to link changes at the molecular/cellular levels to alterations in neural circuits for birdsong/human speech. We also have collaborations with researchers working in mouse models to understand shared molecular pathway for vocal function. The end goal is to leverage the advantages offered by each species and an array of biological tools to further advance our understanding of how the brain controls vocalizations. Our laboratory website, including an updated publication list, can be found at: https://julieemiller.lab.arizona.edu/content/publications-abstracts

Our lab investigates how the ecology of a species shapes patterns of variation at multiple levels (genes, pathways, transcriptomes, genomes, physiology, behavior and life history), how populations adapt to environmental shifts (natural or human created), how genetic architecture can dictate the evolutionary trajectory of populations, the implication of ecological adaptation in the process of speciation and the role of sexual selection and sexual conflict in the evolution of reproductive incompatibilities. Our research revolves around these fundamental aspects of evolutionary biology. We work on a group of cactophilic Drosophila that inhabit the deserts of North America. These Drosophila species are an excellent system to study given that their ecology is well understood and the fact that we can perform many genetic, genomic, manipulative and life history experiments. In addition to utilizing the cactophilic Drosophila system we have ongoing projects on the agrigenomics of the agricultural pests, Drosophila suzukii (spotted wing Drosophila) and Helicoverpa zea (corn earworm). Keywords: Evolutionary, ecological and agricultural genomics

Joanna Masel, D.Phil., is a Professor of Ecology & Evolutionary Biology, applying the tools of theoretical population genetics to diverse research problems. Her research program is divided between analytical theory, evolutionary simulations, and dry lab empirical bioinformatic work. The robustness and evolvability of living systems are major themes in her work, including questions about the origins of novelty, eg at the level of new protein-coding sequences arising during evolution from "junk" DNA. She also has interests in prion biology, and in the nature of both biological and economic competitions. She has won many awards, including a Fellowship at Wissenschaftskolleg zu Berlin, a Pew Scholarship in the Biomedical Sciences, an Alfred P. Sloan Research Fellow, a Rhodes Scholarship, and a Bronze Medal at the International Mathematical Olympiad.

Xianchun Li, PhD, is interested in understanding the physiological, biochemical, molecular and evolutionary bases of fundamental processes in the life history of insects such as embryonic polarity, metamorphosis, developmental commitment, host usage and environmental adaptation. One focus of his research is to elucidate the reciprocal signaling interactions between plants and insects, and the resulted on-going defense (in the case of plants) / counterdefense (in the case of herbivorous insects) phenotypic arm race over ecological time scale, with emphasis on the genetic machinery that percepts and transduces the reciprocal cues into genome and regulate defense / counterdefense phenotypes. Working systems include Helicoverpa zea, the corn earworm, a polyphagous noctuide of economic importance, and Drosophila melanogaster, the fruit fly, a model organism. State of arts and traditional techniques are combining to identify the cues and to uncover the signaling transduction cascade that links environmental cues, gene expression and the resulted defense/counterdefense phenotypes. This research may lead to characterization of genes for designing new insecticides and/or genetically modifying crops. The second focus of Dr. Li’s research is to define, globally, the regulatory triangle between nuclear receptors (NRs), their ligands, and cytochrome P450s (P450s) in Drosophila melanogaster. Nuclear receptors (NRs) constitute a transcription factor superfamily that has evolved to sense and bind endogenous (e.g., hormones) and/or exogenous (e.g., naturally-occurring or synthetic xenobiotics) signal compounds, resulting in differential expression of particular target genes, which underlies a range of fundamental biological processes, including growth, development, reproduction, behavior, host usage, and environmental adaptation. Many of those cue chemicals, namely NR ligands, are synthesized and/or metabolized by members of the P450s gene superfamily, whose expression may be regulated by certain NRs. Bioinformatics analyses as well as systematic functional genomic techniques such as microarray, X-ChIP, mutation and ectopic expression will be combined to define the genome-wide regulatory interaction loops between NRs and P450s as well as to assign, at least partially, functions of individual NRs and P450s in the life history of fruit fly. Given the evolutionary conservations of homologous NRs and P450s between vertebrates and invertebrates, the results obtained in this project are expected to provide insights into the reciprocal regulatory interactions between NRs and P450s in other animals including humans as well as to provide great insights into new avenue for human NR ligand identification and NR-related drug design. The third focus of his research is to investigate the molecular mechanisms of Bt and conventional insecticide resistance, which is a major threat in current IPM system. In collaboration with Dr. Bruce Tabashnik, Timothy Dennehy, and Yves Carriere in our Department, Dr. Li is going to compare Bt toxin binding affinity and other defects of natural (s, r1, r2, r3) and artificial mutant PBW (Pink Bollworm) cadherin proteins and thus define the key functional domains of PBW cadherin.

What we’re interested in: For all vertebrates, from mice to humans, vaccine-induced and naturally primed immunity to pathogens require that coordinated, multi-cellular responses emerge from a myriad of ‘conversations’ that take place between cells of the immune system. These conversations occur via cytokines and chemokines that are secreted by one cell and detected via receptors on other cells. They also occur via direct contacts between membrane-bound molecules at the interface between two cells. Ultimately, these conversations are responsible for insuring that an appropriate immune response occurs in the appropriate place, and at the appropriate time, to fight an infection without inducing an inappropriate response to commensal organisms or self-antigens. The molecules on T cells that are involved in these conversations include but are not limited to: the T cell receptor (TCR), which provides clonotypic antigen specificity to T cells; the CD3δε, γε, and ζζ signaling dimers that connect the TCR to the intracellular signaling machinery; the CD8 and CD4 coreceptors that provide major histocompatibility molecule (MHC)-restriction for T cells that recognize antigenic peptides bound to class I or II MHC, respectively; and costimulatory molecules, such as CD28, that provide information about the activation state of an antigen presenting cell (APC) and thus the context in which an antigen occurs. We are interested in understanding how the individual contributions from this chorus of molecules are integrated to achieve the critical balance between tolerance of self-antigens and protective immunity against pathogenic infection. Specifically, we are working to understand how the information that is critical for T cells to decide if and how they should respond to antigen is conveyed from an antigen presenting cell (APC) to a T cell. We are using a variety of classic molecular, cellular, and biochemical techniques, as well as more modern live cell imaging approaches, to probe the molecular mechanisms involved in these processes. We are also developing mouse model systems to determine how individual mechanisms contribute to T cell responses in vivo during pathogenic infection or autoimmunity. Altogether, our work is aimed at increasing our basic and practical appreciation of T cell responses and regulation.

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.

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.