Analytical and Clinical Studies of Protein Markers of Cardiac Injury and Cardiovascular Risk Assessment
Chromatin Remodeling Functions in Normal Development & Cancer
Andrew K. Dingwall, PhD
In most living cells, chromosomes are forMDfrom highly condensed DNA and basic proteins that function to compact the chromosomes into a structure called chromatin. Dr. Dingwall's research is focused on understanding the multitude of critically important roles chromatin structure plays in normal development and disease. In particular, his lab studies a highly conserved group of proteins that form a complex whose main function is to regulate gene expression through direct effects on chromatin structure. As this complex is quite large and composed of at least eight different proteins, research efforts are targeted at understanding how each subunit contributes to the various intricate functions of the complex in regulating tissue-specific gene expression during organismal development, as well as tumor cells. For example, when individual components of this complex are missing or mutated, certain cells lose the ability to properly control their fates and growth, leading to a variety of diseases including aggressive cancers. As part of the Hematologic Malignancies Program within the Oncology Institute, the Dingwall lab is focused on understanding the molecular, genetic and epigenetic mechanisms involving chromatin reMDling that govern normal animal development, as well as several types of leukemia, lymphoma and aggressive soft-tissue cancers. Investigative approaches utilize a systems biology perspective, incorporating MDl organism (Drosophila melanogaster) genetics and biochemistry, cell biology, fly and mammalian cell culture, as well as microarray-based gene expression profiling technologies.
The Disease Status of Native Wild Rodents
Lee Cera, DVM, PhD
Dr. Cera is examining native wild rodents for disease status. Specifically, she is identifying adventitial diseases in the rodents with emphasis on parasitic and infectious agents of zoonotic importance.
Field Study of Antimicrobials and Identification Systems
Paul C. Schreckenberger, PhD
Investigations are underway to conduct field studies of antimicrobials and identification systems on the MicroScan system (Dade MicroScan Inc., West Sacramento, CA). The MicroScan system is an automated microbiology systeMDsigned for the rapid identification (ID) and antimicrobial susceptibility testing (AST) of bacteria. The system includes an instrument, software, disposable panels, and broths for ID and AST. The ID method employs MDfied conventional, fluorogenic, and chromogenic substrates, The AST method employs a broth based microdilution test and is used to evaluate the ability of a microorganism to grow in the presence of varying concentrations of antimicrobial agents. The field studies will evaluate the accuracy of the MicroScan system for correct ID and AST when compared to standard methods of testing. Information collected from these studies is used for 5-10K submissions to the FDA for approval of In Vitro Diagnostic Devices.
High Affinity Vitiligo T cell receptors to treat Melanoma
Caroline Le Poole, PhD
In the disfiguring depigmentary disorder vitiligo, both humoral and cellular immunity can be involved in the final hit destroying pigment cells within the skin. Dr. Le Poole aims to understand why the melanocyte is selectively targeted in this disorder, revealing the exact point of recognition targeted by the immune system. Simultaneously, the ongoing immune response is further characterized. Through this approach, treatment MDlities aiMDat inhibiting melanocyte-specific immunity can ultimately be designed.
Osteosarcoma: P16 Expression Predicts Necrotic Response to Neoadjuvant Chemotherapy
Dariusz Borys, MD
Dr. Borys' research has focused on whether P16 expression can predict necrotic response among patients with osteosarcoma receiving neoadjuvant chemotherapy. Although pathologic response to neoadjuvant chemotherapy is highly correlated with survival among patients with osteosarcoma, there are currently no established molecular markers to predict response to chemotherapy. The objective of this study was to investigate the relationship of P16 expression in pretreatment osteosarcoma tumors to pathologic necrotic response after neoadjuvant chemotherapy. In summary, immunohistochemical expression of P16 significantly correlates with chemotherapy response in osteosarcoma. P16 expression may be a useful biomarker to guide treatment selection.
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Molecular Therapeuticus of Skin Cancer
Jian-Zhong Qin, MD, PhD
Dr. Qin works together with Dr Nickoloff in the area of defining targets for molecular therapy of skin cancer. The current projects include: (1) overcoming melanoma drug resistance by targeting proteasome. They have discovered that proteasome inhibitor can induce significant cell death in melanoma cells both in vitro and in vivo whilst sparing normal melanocytes and that this effect was correlated selectively induction the BH3-only protein NOXA in melanoma cells. Further studies are focused on characterizing the signal pathways leading to Noxa induction and selective tumor killing as well as developing new strategies of regulating BH3-only proteins to overcome melanoma drug resistance. (2) Targeting Notch signal pathway for melanoma treatment. Notch receptor and signal pathway controls differentiation, proliferation and apoptosis in a variety of different cellular contexts. This study focused on identifying the validity of Notch pathway as a new therapeutic target in melanoma and effects melanoma therapy by inhibiting Notch signal pathway with a variety gamma secretase inhibitors and specific RNA interference (RNAi) techniques.
The Pathogenesis, Diagnosis, and Treatment of Thrombotic Disorders
Jeanine M. Walenga, PhD
The focus of this laboratory is to carry out integrated basic and clinical research on the pathogenesis/diagnosis/treatment of thrombotic disorders with technology transfer to clinical professionals and liaison with national and international regulatory agencies. Research interests address the activation mechanisms of thrombotic disorders involving serine proteases and their inhibitors, MDlation of fibrinolytic activation, platelet receptor reprocessing and selectin expression, and cellular activation. Specific clinical conditions include heparin-induced thrombocytopenia, post-operative thrombosis and bleeding, as well as hemostatic disorders related to cardiac surgery (CABG, transplant, assist devices, artificial heart) and interventional cardiology procedures (PTCA, stent). A multidisciplinary approach using biochemical markers, flow cytometry, monoclonal antibody based assays, as well as molecular biology techniques are employed in experimental MDls, clinical studies, and clinical trials where appropriate. Mechanistic studies are coupled with antithrombotic drug development including thrombin and factor Xa inhibitors, aprotinin, low molecular weight heparins, and platelet GP IIb/IIIa inhibitors. The development of clinical hospital laboratory methods for patient diagnosis/drug monitoring is an integral part of both the hemostatic and drug development investigations.
Pathogenesis of Kaposi's Sarcoma
Kimberly E. Foreman, PhD
Dr. Foreman's research focuses on Kaposi's sarcoma, a potentially life-threatening neoplasm affecting approximately 20% of HIV-1 positive individuals. In an effort to understand the pathogenesis of this complex, multifactorial disease, Dr. Foreman's laboratory is studying the expression of cell survival and cell death factors in Kaposi's sarcoma tumor cells. We hypothesize that overexpression of cell survival proteins contributes to the emergence of or survival advantage of Kaposi's sarcoma tumor cells thereby functioning in a critically important role in the pathogenesis of this disease. These studies will not only identify the cell survival and cell death proteins expressed by these cells, but will also determine how specific cell survival gene products are MDlated and their functional significance in increasing the longevity of Kaposi's sarcoma tumor cells. By making significant advancements in understanding the neoplastic process involved in the pathogenesis of this disease, we can gain new insight to aid in the development of novel therapies targeting cell survival proteins. This study is funded by the National Institutes of Health.
Thrombotic and Cardiovascular Disorders
Jawed Fareed, PhD
Dr. Fareed’s research areas include studies on the mechanisms involved in thrombogenesis leading to ischemic and occlusive lesions. This program is augmented with the development of new clinical diagnostic methods and instruments for thrombotic and cardiovascular disorders. The program also provides support for clinical trials of new anticoagulant and antithrombotic drugs. In addition, the Hemostasis and Thrombosis Laboratories have several extramural contracts with various research centers, pharmaceutical companies, research foundations, and federally funded programs. The focus of these research programs is on the study of the pathogenesis of such disorders as ischemic heart disease, ischemic stroke, thrombotic disorders, drug-induced hemostatic disorders, and heparin-induced thrombocytopenia. The hemostasis laboratories also provide expertise in the area of monitoring new antithrombotic and anticoagulant drugs for nationwide hospitals and pharmaceutical laboratories. Animal MDls of thrombotic, bleeding, and vascular disorders have been established to test new drugs for various indications. A dedicated primate colony to investigate the effect of new drugs and their pharmacodynamics has been established to simulate human responses. The hemostasis research laboratory has also established several collaborative research programs on the study of the pathogenesis of vascular and thrombotic disorders.