Speakers' Abstracts & Bio-Summaries
Nancy A. Muma, Ph.D., Professor and Chair, Department of Pharmacology and Toxicology, University of Kansas
"SUMOylation in the Treatment of Depression"
Depression and anxiety are strongly associated with abnormal brain serotonin especially serotonin 1A (5-HT1A) receptor signaling. My team discovered that 5-HT1A receptors are SUMOylated in rat brain. Small Ubiquitin-like Modifier (SUMO) proteins are ubiquitin-like polypeptides that can be covalently conjugated to cellular proteins in a manner similar to ubiquitylation. SUMOylation can alter protein –protein interactions as well as protein function and localization. Our data suggest that SUMO1 modified 5-HT1A receptors are inactive; the SUMOylated receptors are not capable of binding to an agonist and do not co-localize with Gαz, a Gα protein to which they functionally couple. Drug treatments that reduce 5-HT1A receptor signaling including agonist treatment and treatment estradiol, increase the SUMOylation of 5-HT1A receptors, consistent with our data suggesting that SUMOylated 5-HT1A receptors are inactive. To further explore the regulation and impact of SUMOylation on 5-HT1A receptor signaling, we used a mouse neuroblastoma (N2a) cell culture model to determine the enzymes which regulate SUMOylation of 5-HT1A receptors and to determine the sites on the 5-HT1A receptor protein that are SUMOylated. We determined which PIAS proteins which facilitate SUMOylation and which SEMP proteins which can deSUMOylate proteins. Transfected PIAS constructs expressed in the membrane and cytosol fractions of N2a cells and various PIAS constructs showed different expression levels. PIASxα significantly increased the SUMOylated 5-HT1A receptors compared to other PIAS proteins. Preliminary experiments suggest thtat overexpression of SENP2 protein reduces SUMOylated 5-HT1A receptors. In the second set of experiments, we examined the expression of PIAS proteins in rats treated with a 5-HT1A receptor agonist or agonist and estradiol which increase 5-HT1A receptor SUMOylation to test the hypothesis that an increase in expression of PIASxα or a decrease in expression of a SENP protein regulate the change in receptor SUMOylation. The results show an increase in the expression level of PIASxα in rats co-treated with estradiol and the 5-HT1A receptor agonist 8-OH-DPAT compared to the expression level of PIASxα vehicle treated groups. Together, these data suggest that PIASxα plays a role in increasing SUMOylation of 5-HT1A receptors. Targeting PIASxα in the SUMOylation of 5-HT1A receptors could have important clinical relevance for the therapy towards the neuropsychiatric disorders such as depression and anxiety.
Nancy A. Muma holds a bachelors degree in psychobiology from Western Maryland College obtained in 1979, and a M.S. in neuropsychopharmacology in 1982 and a Ph.D. in 1985 in pharmacology from the University of Louisville. She completed post-doctoral work in neurotoxicology at The Johns Hopkins University School of Hygiene and Public Health and a fellowship in neuropathology at the Johns Hopkins University School of Medicine. In 1989, she joined the faculty of the Pathology Department at the Johns Hopkins University School of Medicine as an Assistant Professor with an adjunct appointment in the Department of Environmental Health in the Johns Hopkins University School of Hygiene and Public Health. In 1992, she moved to the Department of Pharmacology at Loyola University Chicago, Stritch School of Medicine and worked her way up through the academic ranks to become a Full Professor in 2001. She moved to the University of Kansas School of Pharmacy to become the Chairman of the Department of Pharmacology and Toxicology in 2007. Her research interests include neurodegenerative diseases especially Alzheimer’s disease, Progressive Supranuclear Palsy and Huntington’s disease as well as serotonin neuropharmacology focusing on depression and schizophrenia. Dr. Muma is the author or co-author of more than 90 research articles and review articles on these topics. She has served on several NIH Study Sections as a member or chairman, served on the editorial board for the Journal of Neuropathology and Experimental Neurology, the Journal of Experimental Pharmacology and Frontiers in Alzheimer’s Disease, and is currently a Councilor for the International Society for Serotonin Research. She has been a co-investigator or sponsor on 15 and a principal investigator on 6 NIH grants as well as principal investigator on numerous grants from foundations. She has been the dissertation advisor for 14 Ph.D. students and thesis advisor for 5 M.S. graduate students. These students have gone on to successful careers as faculty, science writers, and patent law advisors.
J. Christian J. Ray, Ph.D., Assistant Professor, Center for Computational Biology and Department of Molecular Biosciences, University of Kansas
"Regulation of Bacterial Growth in Discrete Steps and Structured Lineages"
Prodigious growth is a defining feature of bacterial life. Systems of networks change growth rates in bacteria dynamically in response to changing environments. This includes surviving stresses such as antibiotics and starvation via slowing of growth. Phenotypic heterogeneity allows a small fraction of cells to enter growth arrest by randomly crossing an internal molecular threshold, a form of bet-hedging that allows the population of cells to survive even if future environments are inhospitable to actively growing cells. Therapeutic targeting of growth arrested bacteria is a critical emerging strategy during the current rising problem of antibiotic resistance and the continued challenge of treating stubborn, chronic infections. We are taking a multifaceted approach that has opened new avenues for understanding persister formation with time-lapse microscopy and computational models. Our experiments have shown a novel persister-forming condition. In this condition, bacterial cells undergo discrete shifts in growth rate that correspond to fast molecular reshuffling events. Analysis of cellular lineages in these conditions demonstrates that cellular transitions into growth arrest are not statistically independent: closely related cells are more likely to transition together. Computational models reproduce lineage correlations with a remarkably simple set of assumptions, and set an upper limit to the amount of heterogeneity in growth rate that is possible in a population of cells. We discuss implications of the novel persister phenotype for pathogens surviving in changing environments, and new questions raised by our results.
Christian Ray received his Ph.D. from the University of Michigan in Microbiology and Immunology and did postdoctoral work in computational systems biology at Rice University and in experimental synthetic biology at M.D. Anderson Cancer Center. He is now Assistant Professor in the Center for Computational Biology and the Department of Molecular Biosciences at the University of Kansas.
Dr. Ray’s group's scientific work uses tools from synthetic biology, mathematical modeling, microbiology, and evolutionary biology to understand how cells sense, compute, and respond to their environment at multiple scales.
Frank J. Schoenen, Ph.D., Associate Research Professor, Higuchi Biosciences Center, University of Kansas; Medicinal Chemist, Target Acceleration Group, Lead Development and Optimization Shared Resource, University of Kansas Cancer Center
"Development of Metarrestin, a Disassembler of the Perinucleolar Compartment (PNC)"
From any perspective, pancreatic cancer is a deadly disease. The American Cancer Society estimated 53,070 new cases and 41,780 deaths from pancreatic cancer in the United States for the year 2016. Disease survival rates have not changed significantly over the last 30 years. Between 72 and 90 percent of patients succumb to pancreatic cancer within the first year after receiving a diagnosis, even patients for which an early disease-state was treated with complete surgical resection, as the disease inevitably recurs. The failure of treatment efforts is partly due to the lack of strategies that are effective against metastasis, the cause for most pancreatic cancer deaths. We have developed a first-in-class small-molecule, Metarrestin, which selectively blocks metastasis in an orthotopic pancreatic metastatic cancer model without detectable adverse effects on tested animals. Metarrestin was optimized starting from two compound-hit chemotypes identified through a phenotypic, high-content, high-throughput screen for small molecules that reduced the prevalence of the perinucleolar compartment, a cellular subnuclear structure whose prevalence reflects the metastatic capability of cancer cells. Metarrestin has very good oral bioavailability and tolerability, and also shows promising activity in metastatic xenograft models of prostate cancer and breast cancer. The rationale for this new therapeutic approach and the associated medicinal chemistry, pharmacokinetic and biological studies will be summarized.
Frank Schoenen, is Associate Research Professor in the KU Higuchi Biosciences Center (HBC) and Medicinal Chemist within the Target Acceleration Group (TAG) and the Lead Development and Optimization Shared Resource (LDOSR) in the University of Kansas Cancer Center (KUCC). He received the Bachelor of Science degree in chemistry from Rockhurst College, Kansas City, MO, his doctorate in organic chemistry from the University of South Carolina, Columbia, SC, and a US NIH National Research Service Award from the NCI to support postdoctoral studies at Yale University and Harvard University. After postdoctoral studies, he joined GlaxoSmithKline as a medicinal chemist working in the inflammation and oncology therapeutic areas and in high-throughput chemistry at the early stages of drug discovery. In 2005, he returned to academia and joined the NIH-funded KU Chemical Methodologies and Library Development Center as the Associate Director for the Administrative Core and the Director for the Synthesis Core, where he was responsible for overseeing the synthesis, analytical characterization, and distribution of thousands of compounds to academic, government, and private-sector biological collaborators. In 2008, this led to his position as Project Manager, Associate Director, and Chemistry Team Leader for the KU Specialized Chemistry Center, one of two national laboratories funded by the US NIH Molecular Libraries Probe Production Centers Network (MLPCN) to specifically support synthesis and medicinal chemistry aspects of hit-to-probe optimization. In these roles, he provided scientific leadership and management for a diverse portfolio of over 40 MLPCN projects leading to 23 probe compounds. As Associate Research Professor in the HBC and Medicinal Chemist within the KUCC TAG and LDOSR, he brings expertise across translational research to collaborations using small molecules as tools to advance biological understanding and therapeutics discovery.