Research and service
Hanley N. Abramson: During the wet bench research phase of his career, Dr. Abramson was engaged in the design and synthesis of analogs of naturally-occurring bioactive compounds; these endeavors resulted in publications describing work on cardiotonic and estrogenic steroids, azabiotin (the nitrogen isostere of the vitamin biotin), and antimicrobial pyrones related to nectriapyrone; recent interests focus on approaches to the design of new anthracyclines with the aim of lowering the cardiotoxic potential of these clinically useful antitumor agents through reduced redox cycling.
Deepak Bhalla: Research is aimed at developing and characterizing animal models that simulate health consequences of air pollutants such as ozone (O3) and cigarette smoke in normal populations and in individuals whose lungs are compromised by a co-pollutant, infection or prior inflammation. While the toxicity studies determine the adverse effects of air pollutants in a compromised lung by utilizing sensitive assays, the mechanistic studies identify major factors that influence the inflammatory response and disease pathogenesis. The intervention strategies are aimed at limiting neutrophil recruitment in the lung by antibodies and inhibitors specific for chemotactic signals, cell attachment and cell migration.
Fei Chen: The focus of the Chen lab is to investigate genetic and epigenetic effects of extracellular inducers, such as ROS and cytokines, on the development and progression of human lung and other cancers resulting from exposure to varied agents including mineral dust and carcinogenic metals. The lab employs pharmaceutical and molecular targeting approaches to elucidate intracellular signaling pathways important for genomic and epigenetic alterations that lead to the expression of genes associated with tumorigenesis. A principal goal is to develop cancer-targeting drugs and other agents that are able to interrupt select intracellular regulatory circuits and to repress or delay the transformation of cells and thereby limit carcinogenesis.
Randall L. Commissaris: The overall aim of studies in Dr. Commissaris' laboratory is to further our understanding of the neuroanatomical sites and neuropharmacological mechanisms for the actions of drugs and other chemicals on behavior. For many years, Dr. Commissaris' laboratory has been studying the effects of drugs of abuse and drugs used in psychiatry, with a particular emphasis on drugs used in the treatment of anxiety and depression. More recently, Dr. Commissaris' laboratory has begun studies investigating the behavioral effects of in utero and perinatal exposure to ethanol and environmental compounds such as lead.
George B. Corcoran: Multidisciplinary and translational research interests focus on cellular injury and cell death, as well as factors governing drug and chemical-induced injuries, including drug metabolism and nutrition. Approaches designed to translate basic discoveries to improve human health and safety involve integrated in vivo models, cellular and molecular biology, pharmacokinetics, synthetic chemistry, and retrospective and prospective clinical investigation of human volunteers and patients. Specific areas of investigation include cell death by necrosis and apoptosis, the role of DNA damage in acute cell death, drug and chemical injury to the liver, role of nutrition and obesity in drug and chemical injury, drug biotransformation including by CYPs, and particularly the toxicity of acetaminophen (paracetamol).
Aloke K. Dutta: Our research integrates medicinal chemistry, neuropharmacology, computational chemistry and molecular biology not only to understand the mechanism of action of novel CNS active molecules but also to advance promising leads to preclinical studies. We focus on discovery of novel drugs for the CNS to explore their potential therapeutic application in several neuro-disorders like Parkinson’s disease, depression and drug addiction. Specifically, novel molecules, designed through rational drug design and computational studies, are developed routinely to target monoamine transporters and receptors systems either specifically or non-specifically to produce desired pharmacological outcome. In PD research area we are focused on development of bi or poly-functional molecules to produce neuroprotective treatment agents. In the depression area, we have developed novel triple uptake inhibitors as promising new generation antidepressants. Our research is supported by multiple NIHR01 grants.
Steven M. Firestine: Chemical biology and medicinal chemistry focused on the discovery and elucidation of antiinfective agents. Specific areas of interest include the development of agents targeted to de novo purine biosynthesis, the creation of membrane active antibiotics and the discovery of novel peptidomimetics to inhibit DNA replication in cytomegalovirus.
Fusao Hirata: Our group is the first to characterize annexin A1, a 37K Da protein previously referred as lipomodulin or lipocortin I. This protein mimics some, if not all, of the actions of glucocorticoids, e.g., anti-inflammation and immunosuppression, by inhibiting phospholipase A2. On the other hand, this protein is a major substrate of the oncogenic tyrosine kinases such as c-met and c-src, thereby being involved in cell proliferation and differentiation, but its role in signal transduction remains poorly understood. Our current research deals with translocation and modifications of annexin A1 in nuclei to explore its role in carcinogenesis and cell transformation.
Anjaneyulu Kowluru: Our diabetes research is aimed at: [i] understanding the mechanism[s] underlying glucose-stimulated insulin secretion from normal beta cells. The goal is to identify specific genes that must be regulated by glucose to induce insulin secretion; [ii] identifying specific defects in the glucose-signaling pathways within the beta cell in type 2 diabetes with a goal to identify novel drug targets to rectify these in the diabetic beta cell; and [iii] deciphering mechanisms responsible for autoimmune destruction of the beta cell death leading to the onset of type 1 diabetes. Our goal is to develop beta cells that are resistant to immune attack for use in transplantation treatment of Type 1 diabetes.
Robert T. Louis-Ferdinand: Mechanisms of adaptive responses following sub-acute and chronic exposure to toxicants and therapeutic agents; environmental influences on the development of toxicity.
Olivia M. Merkel: The aim of the Merkel lab is to develop new, safe, and target-specific theragnostic nanomedicines. Specifically, we synthesize and genetically engineer novel nanoscale delivery systems for siRNA which on the one hand have a strong affinity to the cells to be treated. On the other hand and due to their high affinity to the target cells, these delivery systems can be investigated for their ability to serve as diagnostic tools. We use radiolabeling and radioactive imaging techniques to detect circulating or distant target cells, e.g., circulating tumor cells, circulating cells of the immune system, or metastases. Additionally, we are interested in the subcellular fate of the newly developed carrier systems and follow them by confocal microscopy. For therapy, siRNA against transcription factors driving inflammation cascades are encapsulated into nanoparticles and delivered to sites of inflammation.
Anna Moszczynska: Dr. Moszczynska’s lab explores methamphetamine neurotoxicity and the role of ubiquitin E3 ligases, particularly parkin, in neuronal damage involving mitochondria, dopamine D2 autoreceptor, dopamine transporter, synaptic vesicular monoamine transporter 2, and the ubiquitin proteasome system. We propose that decreased Parkin function impairs the proteasome, mitochondria, autoreceptor and transporter in vivo, whereas parkin upregulation protects against neurotoxicity. The lab employs rat models of neurotoxicity, in vivo viral overexpression of parkin, cell and molecular biology, and immunohistochemistry. The goal is to elucidate the role of E3 ligases in pathological states in which dopaminergic systems are affected, such as psychostimulant abuse, Parkinson’s disease, and schizophrenia, in search of better treatments.
David Pitts: The understanding of the physiological and pharmacological properties of central monoaminergic neurons is of general interest, especially as this pertains to neurological and psychiatric diseases and disorders. One focus area examines the effects of xenobiotic exposure on the postnatal development of monoaminergic neurons. Another focus area is the pharmacological characterization of novel drugs that have potential therapeutic actions involving monoaminergic neurons. The study of monoaminergic neurons utilizes electrophysiological techniques, immunohistochemistry, and microdialysis.
Philip L. Pokorski: Clinical interdisciplinary research involving polypharmacy pharmacokinetics and mechanisms; a related interest is the toxicology of drugs of abuse and pharmaceutical agents in forensic deaths; cellular mechanisms of pathologic and disease processes which account for specific symptoms of disease; past research interests include heavy metals toxicology and therapeutic detoxification mechanisms of 2,3-dimercaptosuccinic acid (Succimer, Chemet).
Zhihui Qin: Research interests include drug discovery (prostate cancer, breast cancer and Alzheimer’s disease), chemical toxicology (toxicity and carcinogenesis of reactive metabolite, therapeutic applications of oxidative stress) and drug metabolism (biotransformation). The prostate cancer project focuses on targeting prostate cancer (PCa) cells by combined androgen receptor (AR) antagonism and oxidative stress induction. In this study, elevated intracellular oxidative stress in PCa cells is considered as a co-target with AR. Multifunctional hybrid drugs (conjugative approach) or drug combinations (combinatorial approach) using different AR antagonists and reactive oxygen species (ROS) inducers are tested to kill PCa cells synergistically. Simultaneously targeting multiple oncogenic pathways is likely to improve efficacy, response rate of therapeutic drug and to limit emergence of drug resistance.
Duska M. Separovic: Our research interests are focused on studying the molecular mechanisms underlying cell death evoked by oxidative stress after photodynamic therapy (PDT), a cancer treatment modality. Our long-term goal is to potentiate the efficacy of PDT for cancer treatment. Specifically, we investigate the involvement of sphingolipids in cell death post-PDT. The significance of our research is in that it should reveal: new molecular targets that will lend themselves to therapeutic interventions; new sphingolipid analogs that advance PDT therapeutic successes.
Timothy L. Stemmler: The Stemmler lab is focused on obtaining a molecular/atomic level characterization of the structure and function of biomolecules that participate in cellular metal homeostasis pathways. Metals are essential for cell (and organism) viability, however in excess they often become toxic. A detailed understanding of the metal transport and delivery mechanisms used to coordinate balanced metal homeostasis would benefit the development of treatment strategies aimed at correcting conditions seen in human disorders where these pathways are deficient. Our laboratory utilizes a variety of biochemical, spectroscopic and structural techniques to elucidate the structure/function relationships for metalloproteins and metal bound biomolecules, with the goal of answering important questions related to the mechanistic details of metal homeostasis pathways. Our XAS studies are performed at the Stanford Synchrotron Radiation Laboratory (SSRL) and at the Brookhaven National Laboratory under proposals that are already approved, while NMR, ITC, ICP-MS, fluorescence and stop flow studies are performed in house using instrumentation purchased in part from my NIH funding.
Henry C. Wormser: Synthesis, antimicrobial and cytotoxic screening of a number of 1,4-dihydroxy and 1,4-diamino anthraquinones as well as DNA binding studies of synthetic anthraquinones related to antineoplastic anthracyclines. Structure determination of natural products of biological interest with the intent to develop and synthesize more active analogs. Involvement in the development of the original Wayne State University College of Pharmacy add-on PharmD curriculum and of the current Physician Assistant Studies program.
Zhengping Yi: Insulin resistance lies at the base of the array of diseases or pre-disease conditions known as the Metabolic Syndrome, including obesity, dyslipidemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, and some cancers. Dr. Yi’s research focuses on a better understanding of the basic biology of insulin signaling and the etiology of insulin resistance. Dr. Yi and his group are using a combination of clinical, biological, and proteomic approaches to better comprehend insulin signaling and the associated problems that occur with obesity and T2D. Studying insulin signaling in humans is challenging. Dr. Yi’s laboratory has developed state-of-the-art techniques that can be used to better define and understand the effect of insulin in key metabolic tissues in humans such as skeletal muscle. These approaches are useful models for studying cell signaling pathways in general, and especially their regulation by protein phosphorylation and protein-protein interactions. In addition to directing his independent laboratory working on insulin signaling both in vitro and in vivo, Dr. Yi also directs the Proteomics Laboratory in the College of Pharmacy. Proteomics offers the capability to simultaneously quantify multiple proteins, protein-protein interactions, and protein phosphorylation, providing a better picture of complex protein networks.