Projects

• Role of PI-3 Kinase and PKC in the Mechanisms of Human IL-17

Samuel E. Adunyah, Ph.D.
IL-17, which has been implicated in cervical, ovarian, breast and prostate cancer, activates key signaling pathways including PI-3 kinase/Akt, which in turn activate STAT1 and STAT3.  This proposal examines the exact mechanism by which IL-17 regulates the function of STAT3 and if activation of Akt by IL-17 promotes cancer cell survival.

• Serotonin Dysfunction and Parkinson’s Disease

Twum A. Ansah, Ph.D.
Parkinson’s disease is characterized by the degeneration of dopamine-producing neurons, although the clinical features are not recognized until ~70% of striatal dopamine is lost. To evaluate the early steps in the development of Parkinson’s, a mouse model employing MPTP will be used to determine regional dopaminergic and serotonergic cell loss, and 5-HT2A receptor antagonists ameliorate motor deficits.

• Regulation of the Expression of G-Protein G

Ifeanyi J. Arinze, Ph.D.
Anti-proliferative inhibitors of histone deacetylases such as valproate and butyrate are used in clinical trials against various forms of cancer. Among their actions, these compounds increase the production of reactive oxygen species that in turn activate redox-sensitive transcriptional factors, such as Gαi2and Nfr2. Using K 562 cells, current studies will examine the mechanisms responsible for the nuclear import of Nfr2 following cytoplasmic activation, and for the turnover of Gαi2 .

• Molecular Analysis of Leishmania Kinetoplast RNase H

Gautam Chaudhuri, Ph.D.
Leishmaniasis affects some 12 million people around the world. As a kinetoplast-associated type II ribonuclease H (RNase HIIC) from Leishmania mitochondria is essential for the growth of this parasite, it may be viewed as a potential molecular target for anti-leishmanial chemotherapy. Thus this proposal aims to characterize both the recruitment of RNase HIIC into the kinetoplast protozoan network and into Leishmania mitochondria.

• Mitochondrial Protein Import Machineries from Trypanosoma brucei (T.brucei)

Minu Chaudhuri, Ph.D.
African trypanosomiasis is caused by the parasitic protozoa, T. brucei. To functionally adapt to both insect and mammalian hosts, the mitochondrial machinery, and in particular the mitochondrial import machinery of T.brucei also needs to adapt.  Prior studies showed that trypanosome alternative oxidase uptake into mitochondria (MT) of the bloodstream form of the parasite depends neither on the MT membrane potential nor outer MT membrane proteins. The intent of the present proposal is to clone and determine the functional role of outer and inner MT membrane translocases (TOM, TIM) and to study the import efficiency of isolated MT from both bloodstream and procyclic forms of the protozoa.

• Passive Immunity to S. Pneumonia in an At-Risk Population (pilot)

Shahana A. Choudhury, M.D.
In the first few months of life, infants are though to be protected against pathogens such as Streptococcus pnuemoniae due to a passive immunity derived from the mother, yet African American infants are subject to an enhanced morbidity and mortality due to such pathogens. This pilot study looks at some of the biological and environmental factors that may be associated with this disparity.

• The Role of Oxidative Stress in Atherogenesis

ZhongMao Guo, M.D., Ph.D.
Based on his previous findings that oxidized lipids induce injuries to vascular cells, and that antioxidants and calcium antagonists are cytoprotective, this study asks if overexpression of antioxidant enzymes reduces: a) lipid peroxidation, b) the response of vascular cells to oxidized lipids; and c) the development of atherosclerosis.

• Binding Proteins and Oral Streptococcal Endocarditis

Robert Holt, Ph.D.
To better understand the pathogenesis and possible prevention of infective endocarditis cause by orally derived S. mutans, this project examines the properties of an S. mutans-derived 170 kDa protein that binds fibronectin and that also may represent a therapeutic target against infective endocarditis. The long-term goal is to determine what bacterial cell surface molecules are involved in cell colonization and invasion of damaged endocardial tissue.

• Noradrenergic Modulation of Trigeminal Nociception

Sukhbir Mokha, Ph.D.
Painful syndromes and disorders such as temporomandibular joint, migraine, trigeminal neuralgia, irritable bowel syndrome, and rheumatoid arthritis are more prevalent in women than men. This project examines a model in which women have a decreased endogenous inhibitory control of pain mechanisms brought about by G-protein coupled receptors, and proposes genomic and non-genomic-based studies to determine why.

• Thrombin-Induced Regulation of Nitric Oxide (NO) Production

Evangeline D. Motley, Ph.D.
Preliminary experiments have shown that thrombin, a key molecule in the progression of vascular disease, phosphorylates endothelial NO synthase (eNOS) through a PI-3  kinase/Akt-independent pathway in bovine aortic endothelial cells. The primary goals of this project are to identify the specific kinases and signaling proteins involved in this pathway and to determine the role of thrombin-induced eNOS phosphorylation and activation in the regulation of NO production.

• Mechanism of Differential Gene Expression in Alphavirus

Ramasamy Raju, Ph.D.
Sindbis virus (SIN) is a mosquito-transmitted human RNA virus that is used in this study to examine the evolution of the RNA virus genome and its replication. Thus far the PI has determined that SIN replication does not require an evolutionarily conserved RNA motif at the 3’ end of the genome; this project examines the role of 5’ RNA motifs in SIN replication as well as SIN genome repair processes.
 

• Resveratrol Modulation of Benzo(a)pyrene (BaP) Metabolism

Aramandla Ramesh, Ph.D.
BaP is an environmental toxin that among its many effects, can be carcinogenic in both humans and in animal models.  Among its cellular actions is the production of BaP-DNA adducts that if not repaired prior to DNA replication, may lead to mutations and ultimately, to cancer. Resveratrol is a naturally occurring phytoestrogen that has cardioprotective, anticancer and antioxidant properties. This study examines if imprinting with resveratrol (given to rat pups in first week following birth) alters the metabolism of BaP, and BaP adduct formation, when BaP exposure is roughly two months later.

• Cellular Genes Required for Trypanosome Infection

Fernando Villalta, Ph.D.
One-third of individuals infected with T.cruzi die of Chagas’ disease, a disease that affects the cardiovascular, intestinal and nervous systems. The overall intent of this study is to identify genes involved in the early phase of cellular infection by T. cruzi, and to determine the role of those gene products in the cellular steps of infection. Four genes are targeted in this study: host cell laminin γ 1 and thrombospondin-1, and a T.cruzi cell surface casein kinase II substrate (Tc-1), and a lectin-like oxidized low density lipoprotein receptor (LOX-1) which mediates parasite binding to host cells.