Department of Pathology and Laboratory Medicine

Selected Current HRS Projects

• Fecal Microbe Transplant for IBD
  • Conventional therapies for Inflammatory Bowel Disease generally center on immune modulation. Immune development and activation have recently been related to the collective gut microbial community, the microbiome.  IBD patients harbor a distinct gut microbiome that is predictably different and less diverse when compared to healthy individuals. While it is unknown if this dysbiosis is etiologic or a result of the disease process, it is felt to represent a new therapeutic target.  Fecal bacteriotherapy (FBT) enables alteration of the gut microbiome through transplantation of a complete bacterial ecosystem from a healthy individual.  It is hypothesized that the resultant microbial change can induce a shift in host immune response away from autoimmunity.  Early reports of IBD patients successfully treated with fecal microbe transplant (FMT) exists, however well designed prospective studies are lacking.  This prospective, blinded randomized control study assigns patients with mild to moderate Ulcerative Colitis, maintained on standard therapy, to either an FMT arm or a control arm.
• Dengue Fever Study
  • Investigators at UVM, along with collaborators at the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health and Johns Hopkins Bloomberg School of Public Health, have been working since 2008 to develop a dengue vaccine that will protect against all four dengue strains. The team’s latest research, published in Science Translational Medicine, reports promising results from clinical trials on a new vaccine that is very effective at preventing dengue infection and is likely to require only a single dose. The HRS works closely with the Vaccine Testing Center, Infectious Disease department and the Microscopy Imaging Core Facility at UVM to support the histological needs of this study.  Skin samples infected with Dengue Fever are processed and tested at our facility.  A series of staining and imaging techniques are used to provide the principal investigators with a comprehensive, 3-D image of their sample that highlight specific cells involved with Dengue Fever and vaccine.
• Potential Role of Canobacteria in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)
  • The primary etiologic factors leading to the sporadic (non-familial) form of the lethal neurodegenerative disease amyotrophic lateral sclerosis (ALS) remain unknown. One important and well-studied environmental risk factor/trigger for ALS is the cyanobacterial derived toxin, β-N-methylamino-L-alanine (BMAA), that has been previously linked to high rates of ALS in Guam well over 50 years ago. In collaboration with researchers at Dartmouth Hitchcock Medical Center, the team plans to look at the aerosol exposure route of cyanobacterial exposure which, based on demographic and biological studies, appear to be the most significant exposure route for humans. Researchers hypothesize that aerosolization of cyanobacteria is measurable through a variety of techniques foremost in tissue samples from patients with bloom exposures that will have levels of cyanobacteria (e.g. respiratory tract) that are detectable by PCR and ELISA assay.
  • Exposure evaluation will be determined by evaluating postmortem lung, brain and spinal cord samples from both high and low risk subjects for evidence of cyanobacterial exposure, BMAA concentrations and degree and type of neurodegeneration. Researchers will evaluate the histology of CNS tissue in ALS patients and controls to see if there are differences between cyanobacteria exposure levels and histological abnormalities assuming that exposure may promote neurodegenerative changes. Ths approach is innovative; it is the first attempt to evaluate the risk associated with aerosolized cyanobacterial exposure and ALS.  Ultimately, if the bacterial toxin is disseminated through aerosol, this information will enable exposure reduction initiatives to prevent this lethal disease.
• Clinical Significance of PPM1a in Colorectal Cancer
  • The transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in many processes in normal epithelial cells. Genetic mutations in TGF-β/Smads signaling pathway are well characterized in colorectal cancers (CRC) and have been focused on TGF-β receptors and Smads. Another critical regulator in the TGF-β pathway is PPM1A, which is a protein phosphatase that dephosphorylates. This phosphatase activity on P-Smad2/3 is essential to prevent hyperactivation of TGF-β signaling in normal cells. Recent studies have shown that PPM1A exhibited tumor suppressor-like effect in cancer cell lines. Our unpublished data showed that loss of PPM1A in pancreatic cancer is a strong predictor for poor outcomes. Loss of PPM1A was significantly correlated with muscular invasion and tumor recurrence in bladder cancer. In current literature, there is no report on the pathophysiological role of PPM1A in human colorectal cancer that is known to bear mutations in the TGF-β signaling pathway genes. It is necessary to understand the pathophysiological function of PPM1A in CRC while these therapeutic inhibitors targeting TGF-β signaling pathway are investigated in clinical trials. In this proposal, IHC for PPM1A, Smad4, and TGF-β1 will be performed on formalin fixed paraffin embedded (FFPE) colon cancer tissue to investigate whether PPM1A is associated with patient outcomes and TGF-β1/Smad4 expression status. The results would provide new insights into the pathophysiological role of PPM1A in CRC, as well as novel prognostic marker for these patients.