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New Pathogen Discovery investigators

Yuan Chang, MD
Contact:
Hillman Cancer Center
5117 Centre Ave Suite 1.8
Pittsburgh PA
Research Interests and Keywords:
  • Tumor viruses
  • Kaposi's sarcoma associated herpesvirus (KSHV)
  • Merkel cell polyomavirus (MCV)
  • digital transcriptome subtraction
  • tumor virus discovery
Summary
The work of our group (jointly directed by Patrick Moore and Yuan Chang) has focused on human tumor viruses since the early 1990s when we identified Kaposi's sarcoma associated herpesvirus (KSHV/HHV8) and showed that this virus was causally associated with Kaposi's sarcoma, the most common AIDS-related cancer in the United States and the most common malignancy in parts of Africa. We sequenced the KSHV genome, developed serologic assays, determined its prevalence in human populations, and characterized many of its critical viral oncoproteins. We have continued to study virus-host cell interactions in the context of dysregulation of pro-proliferative and anti-apoptotic pathways. We recently identified the seventh human tumor virus, Merkel cell polyomavirus (MCV), from a Merkel cell carcinoma (MCC). We characterized the transcriptional products of MCV and described the early region viral T antigen oncoproteins. Our work has established that MCV causes ~80% of MCC: we determined that the virus is clonally integrated in MCC tumor cells; that human tumor-associated Large T (LT) antigens contain signature truncation mutations; that T antigen proteins are expressed in MCC tumor cells by novel antibodies we developed; and we are the first laboratory to show rodent cell transformation by MCV sT antigen but not the LT antigen. We have identified several novel cellular interactors for MCV T antigens that open new avenues of investigating critical oncogenic signaling pathways. We have focused on many aspects of cancer etiology as modeled through oncogenic tumor viruses.
Patrick Moore, MD, MPH
Contact:
Hillman Cancer Center
Lab 1.8
Pittsburgh PA
Research Interests and Keywords:
  • Human tumor virology (KSHV, MCV and digital transcriptome subtraction)
James Pipas, PhD
Contact:
559B Crawford Hall
4249 Fifth Avenue
Pittsburgh PA
Phone: 412-624-4691
Research Interests and Keywords:
  • Simian virus 40 (SV40)
  • T antigen
  • tumorigenesis
Summary
Simian virus 40 (SV40) belongs to a small collection of viruses that induce tumors. We utilize SV40 as a model system for understanding the molecular events that drive tumorigenesis. Our studies focus on the virus-encoded master regulatory protein, large T antigen. Large T antigen controls several aspects of viral infection including DNA replication, transcription and virion assembly. In addition, T antigen is necessary and, in most cases, sufficient for SV40-mediated tumorigenesis. T antigen induces tumors in rodents and the neoplastic transformation of cells in culture by binding to key cellular proteins that regulate proliferation and survival, and altering their activities. Our basic strategy is to use a combination of genetics and proteomics to identify cellular targets of T antigen and then to use molecular biology and mouse model approaches to understand how these actions contribute to tumorigenesis.
Clayton Wiley, MD, PhD
Contact:
UPMC Presbyterian Hospital
Scaife Hall S701 200 Lothrop Street
Pittsburgh PA
Research Interests and Keywords:
  • Viral infection
  • innate immune response
  • neurodegeneration
  • encephalitis
  • inflammation
  • macrophages
Summary
1. Biomarkers of neuroinflammation: Using positron emission tomography (PET), we have recently imaged macrophage activation in human and non-human primate models of neurological disease. Using a novel radioligand (PK11195) to assess activated microglia in brains of living HIV-infected human and SIV-infected primates, these studies demonstrated the feasibility, but limited sensitivity of PK11195 PET in monitoring central nervous system (CNS) inflammation (Venneti et al., 2008; Venneti et al., 2004; Venneti et al., 2009; Wiley et al., 2009). While performing these PET studies, we took advantage of the study's serial time points to discover biomarkers of neuroinflammation in serum and cerebrospinal fluid. Using unbiased proteomic analysis with SELDI-TOF mass spectrometry, we discovered a highly sensitive and reproducible biomarker of CNS inflammation, chitinase 3-like 1 protein (CHI3L1). We and other groups have since observed expression of CHI3L1 in a broad spectrum of CNS inflammatory diseases (Bonneh-Barkay et al., 2010). 2. Control of neuroinflammation: While of great utility as a biomarker, CHI3L1 is becoming even more important as a member of a new class of proteins mechanistically involved in the control of neuroinflammation. These novel proteins modulate the interaction between inflammatory cells and CNS extracellular matrix. Using transgenic mice where the mouse homolog of CHI3L1 was deleted by homologous recombination, we have examined the role of this protein in animal models of multiple sclerosis (EAE) and traumatic brain injury (Bonneh-Barkay et al., 2012). In both models, deletion of CHI3L1 led to worse clinical and pathological outcome. Current studies in our lab are aimed at elucidating the molecular mechanism by which CHI3L1 limits inflammation and how to mimic its action using small molecules. These studies hold the potential of developing novel therapies to decrease neuroinflammation, potentially supplementing or synergistically interacting with current anti-inflammatories. 3. Age-related neurodegeneration: While intuitively obvious, it warrants remembering that the single most important determinant of neurodegeneration is age. Through extensive collaborations with the Alzheimer's Disease Research Center, we clinically document the neuropathology of AD and related diseases. The beta amyloid hypothesis of AD proposes that toxic fragments or oligomers of beta amyloid mediate neurodegeneration. We and others have explored the capacity of active immunization to eliminate beta amyloid from the aging primate brain (Kofler et al., 2012). Current studies in the lab are examining how lentiviral infection and combined anti-retroviral therapy modulate age related neurological processes and gene expression associated with neurodegeneration. 4. Viral encephalitis: Collaborations with other University of Pittsburgh investigators have allowed us to expand our studies of the brain's susceptibility to viral infections. Our research team has discovered the heightened susceptibility of the brain to aerosol transmission of common viral pathogens. Arboviruses that normally infect through insect vectors cause limited systemic disease, but when delivered through aerosol route, they rapidly cause lethal encephalitis. How the brain's innate immune response and systemic adaptive immunity protect the CNS is a current focus of the lab. We have discovered that host exposure to seasonal influenza determines susceptibility to lethal avian influenza. Newly proposed studies will elucidate the role of innate and adaptive immunity in conferring this protection. Importantly, from a public health perspective, this team is also researching how immunization protects or predisposes to encephalitis.
Joseph Newsome, DVM
Contact:
1050 South TE DLAR
Starzl Biomedical Science Tower 200 Lothrop Street
Pittsburgh PA
Phone: 412-648-8950
Research Interests and Keywords:
  • Immunopathology
  • vaccinology
  • dermatopathology
  • papillomavirus
  • infectious disease animal modeling
Masahiro Shuda
Contact:
UPCI Research Pavilion at Hillman Cancer Center, 1.9
5117 Centre Avenue
Pittsburgh PA
Phone: 412-623-7733
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