Research

Current Research Activities:

Dr. Alvarez-Gonzalez investigates signal transduction pathways, chromatin structure and function, and gene expression in eucaryotes. Emphasis is placed in the molecular biology and biochemical regulation of DNA-replication, transcription, carcinogenesis (DNA damage and repair), and calcium signaling by ADP-ribose transfer enzymes. Current projects include: the characterization of ADP-ribosylated DNA-binding proteins, e.g., DNA-metabolizing enzymes, transcription factors, and histone proteins; as well as the oncogenes and p53 (a tumor suppressor gene) in apoptosis; and the enzymology (molecular, chemical, kinetic and regulatory mechanisms) of poly (ADP-ribose) polymerase, poly (ADP-ribose) glycohydrolase, and ADP-ribose cyclase. Methods and techniques utilized include: tissue culture, cell fractionation, chromatin isolation, protein purification, DNA- replication, transcription, enzyme assays, immunoprecipitation, immunofluorescence, immunoblotting, electrophoresis, autoradiography, radiochemical assays, affinitiy chromatography, HPLC, peptide mapping and mobility shift assays.

Dr. Basu investigates signal transduction, especially in the context of cancer chemotherapy. A major research effort is to investigate how signal transduction pathways regulate cell death by apoptosis. One area of research is to investigate how signal transduction pathways regulate anticancer drug sensitivity and to elucidate the molecular mechanism(s) of drug resistance. Another area of research focuses on tumor necrosis factor- a (TNF) signaling. TNF regulates a wide variety of functions, including cell proliferation, differentiation and cell death. A third area is to define the role of Akt/protein kinase B signal transduction pathway in tumorigenesis and as a target for anticancer therapy. A major focus of her research is on the protein kinase C signal transduction pathway. The ultimate goal is to exploit intracellular signaling systems to benefit cancer therapy.

The major focus of our laboratory is to understand the immune response against intracellular pathogens. Specifically, the gram-positive bacterium, Listeria monocytogenes , is utilized to dissect the roles of T cells, NK cells, NK-T cells, dendritic cells and macrophages during the early, innate immune response that occurs in the spleen and liver. Elucidating the proliferative capacity, cytokine/chemokine secreting potential, localization, and ultimate fate of these and other immune effectors allows us to understand how the immune system coordinately responds to and controls pathogens. Our recent data suggests that although CD8 T and NK cells can respond to Listeria monocytogenes by secreting the cytokine interferon gamma, CD8 T cells play a more prominent role in controlling the infection during the innate immune response. The preferential localization of CD8 T cells with the Listeria monocytogenes lesions provides a mechanism for their increased protective ability. Ongoing studies include: 1) dissecting the localization, effector potential, and fate of NK and NK-T cells in the spleen and liver during the innate response to Listeria monocytogenes , 2) elucidating which factors induce the migration of different immune cells towards the Listeria monocytogenes lesions, and 3) determining which cell types are responsible for secreting interleukin 12 and interleukin 18 (which in turn induce interferon gamma secretion) during the immune response to Listeria monocytogenes .

Dr. Borejdo investigates how muscle works. The key is the knowledge of the interactions between actin and myosin--the two chief protein components of skeletal muscle. We study this interaction by three independent approaches: (i) biochemical approach to determine the proximity of actin to myosin (ii) physico-chemical approach to measure the orientation of myosin in vivo and (iii)
molecular biology approach (cloning mutants of myosin) to establish the role of various amino acid residues in muscle functions.

Dr. Easom's research efforts are directed towards understanding b-cell mechanisms that control b-cell growth/differentation and glucose-dependent insulin secretion. Current goals are: (1) to evaluate the role of Ca2+ dependent protein kinases and phosphatases in insulin gene expression and secretory granule exocytosis; and (2) to achieve the expansion, in culture, of functional human islets for replacement therapies for the treatment of Type I diabetes.

Dr. Gracy's research focuses on components of aging such as Alzheimer's Disease, vision impairment and wound healing. He lectures internationally on aging and age-related medical problems.

Dr. Harris's research interests lie in the area of regulation of carbohydrate metabolism parasitic helminths. The parasite primarly studied is Ascaris suum. Studies involve several enzymes from these parasites, malic enzyme, phosphofrucktokinase (PFK) and fumarase. Current projects involve Z-ray crystallographic studies on malic enzyme and PFK, site-directed mutagenesis of malic enzyme and PFK and other structural studies such as circular dichroism and fluorescenceon these enzymes to determine how the enzymes work.

Dr. Hodge's research investigates the role of lymphocytes and cytokines generated during mycoplasma immunization and infection, and how they impact pathogenesis and protection during mycoplasma respiratory disease. The long term goal of this work is to develop novel approaches for the prevention and treatment of mycoplasma disease, and apply these methods to the study and treatment of other respiratory diseases.

Dr. Jones' research interest include the investigation of how stress affects host immune mediation of chronic disease states with the intention of facilitating comprehensive therapeutic approaches against stress-induced disease pathogenesis.

Dr. Kim's research focus is in elucidating the molecular mechanism of cancer metastasis and developing strategies to reduce/inhibit metastasis. We study the molecular mechanism of prostate cancer metastasis and angiogenesis. First focus is on the molecular mechanism of green tea catechin, epigallochatechin gallate (EGCG), in the regulation of hypoxia- inducible factor alpha expression and VEGF expression. Second focus is on the regulation of cyclooxygenase-2 expression, one of the important players in cancer metastasis and angiogenesis, in bone-metastasizing in prostate cancer cell lines.

Increased plasma levels of high density lipoproteins (HDL) are believed to protect from the development of atherosclerosis. Recent studies, however, suggest that under certain metabolic conditions, many of the important anti-atherogenic properties of HDL may be lost due to the accumulation of lipid peroxides (LPO) transforming HDL into a pro-atherogenic lipoprotein particle. We have developed a method which separates oxidized HDL into fractions, containing low (LOX-HDL), and moderate or high (HOX-HDL) levels of LPO. The focus of our investigation is to identify the conditions and the mechanism(s) under which anti-atherogenic HDL is converted to pro-atherogenic HDL.

Recently we have found that hyperbaric oxygen (HBO: treatment with 100% oxygen at greater than atmospheric pressure) not only suppresses the progression of atherosclerosis in cholesterol fed rabbits without affecting their elevated plasma cholesterol but also accelerates the regression of pre-established atherosclerosis. The mechanism by which oxygen exerts an inhibitory effect on atherosclerosis is presently under investigation.

We have found that the plasma levels of lipid peroxides are elevated in subjects with Alzheimer's disease. The focus of our investigation is to identify the lipoprotein fraction(s) transporting these lipid peroxides in plasma.

Dr. Kulkarnis' current research focuses on the molecular cloning functional expression and genetic analysis of key regulatory enzymes involved in the carbohydrate metabolism in the parasitic nematode Ascaris suum. As a basis for the study of molecular architecture of these enzymes to aid in
rational drug design, site-directed mutagenesis and biochemical characterization of mutant enzyme forms are proposed.

Dr. Lacko's research involves the areas of breast and prostate cancer. He and Dr. Walter McConathy are currently working on a patent-pending system that carries cancer-fighting drugs to targeted areas in the body. Dr. Lacko is also involved in several aspects of cardiac research.

Natural killer (NK) cells are a subpopulation of lymphocytes that play an important role against tumor metastasis and various viral and bacterial infections. NK cells are also involved in the rejection of allogeneic bone marrow transplants. The molecular basis of NK cell recognition and activation by target cells is poorly understood. NK cell functions are controlled by a balance between positive and negative signals through various receptors. We have identified, cloned and characterized several receptors expressed on NK cells. One of the receptors, 2B4, is a member of the immunoglobulin superfamily and is involved in killing cancer cells and virus-infected cells by NK cells. We have determined CD48 as the counter-receptor for 2B4 in both mice and humans.
Recently, we have generated 2B4 knockout mice and this will allow us to study the biology of this molecule in the immune system. We are investigating the signal transduction pathway via 2B4. We have also identified two other novel receptor called LLT1 and CS1. The funcitional role of LLT1 and CS1, in regulating immune responses are being investigated. The major objective of my research laboratory is to decipher the molecular basis of tumor cell recognition by NK cells. The information obtained in these studies will be utilized towards developing new strategies for eliminating tumor cells.

Natural killer (NK) cells are cells of the immune system that form the first line of defense against cancer and infectious diseases. The molecular basis of NK cell recognition and activation by target cells is poorly understood. NK cell cytolytic function is controlled by multiple receptor-ligand interactions. These receptors can transmit either positive or negative signals and belong to the lectin superfamily or immunogloblin superfamily (IgSF). In order to kill the tumor or target cell these NK
cells are te be activated by these receptors. Several receptors expressed on NK cells have been identified, cloned and characterized in our laboratory. Current research activity is about identifying the functional aminoacids involved in the 2B4 - CD48 interactions, functional activity of human 2B4 and its splice variant and functional analysis of novel tyrosine motifis in the cytoplasmic tail of human 2B4. The major objective of our research laboratory is to unravel the molecular basis of tumor cell recognition by NK cell and its multiple receptor ligand interactions.

The long term research focus is the development of a high density lipoprotein based drug delivery system to enhance the delivery of various hydrophobic drugs. Study the mechanism of action of the enzyme lecithin:cholesterol acyltransferase (LCAT), a rate limiting step in reverse cholesterol transport.

Dr. Prokai's current research focuses on (1) understanding the mechanisms by which estrogens and estrogen-derived para-quinols erect a "chemical shield" to protect neurons against reactive species and exploring novel therapies to treat neurodegenerative diseases from the findings, (2) development and use of proteomics in aging research, studying neurodegenerative diseases and in biodefense, and (3) discovering new therapeutic agents based on neuropeptides and peptidomimetics as lead molecules. These multidisciplinary projects rely on his broad technical expertise in state-of-the-art methods in bioorganic, medicinal and bioanalytical chemistry, and on excellent facilities (featuring three mass spectrometer systems including a linear ion trap - Fourier-transform ion-cyclotron resonance hybrid instrument).

Dr. Rao's research interests are in the area of enzymology and protein chemistry, with particular emphasis on enzyme mechanisms, allosteric regulation, x-ray crystallography, protein phosphorylation and dephosporylation. Studies include Aspartate transcarbamylase, a key regulatory enzyme of the pyrimidine biosynthetic pathway,phosphofructokinase, a key allosteric enzyme of carbohydrate
metabolism, and NAD-malic enzyme, involved in energy prodctuin in Ascaris suum, Calcineurin, a calmodulin-dependent protein phosphatase and O-acetylserinesulfhydralase from Samonella typhimurium. These enzymes have been purified and characterized by kinetics, chemical modifications, physiochemical studies including fluorescence, circular dichroism and x-ray crystallography.

Research Interests: Immunology, vaccination, respiratory tract diseases.

Dr. Wu's research interests are in the general area of colony-stimulating factors and their roles in the regulation of myelopoiesis and other biological functions. Current research projects are:
1) Regulation of human macrophage colony-stimulating factor gene expression. The focus of this project is on the transcriptional control under different cytokine stimulation and cyclic AMP attenuation of its expression.
2) Cloning, expression and mechanism of action of a novel leukemia differentiation factor. A new protein factor which can induce in vitro myelomonocytic leukemia cells to undergo terminal monocytic differentiation has been isolated and purified. Its cloning, expression and mechanism of action will be conducted.
3) Role of M-CSF in neuronal development. Neurons produce a glycosaminogylcan conjugated M-CSF. The role of this hematological growth factor in neuron development has been elucidated.
4) Treatment of sickle cell anemia in a transgenic mouse model.