Treatment and Disease Markers for Alpha and Flaviviruses
Collaborating Institution: Utah State University, Logan, UT
Principal Investigator: John Morrey, Ph.D.
Collaborators and Core Labs:
Animal Models Core - CSU
Preclinical Development Core - USUExpected Product: Identification of novel disease markers and therapeutic countermeasures against viral encephalitides.
Introduction:
Our strategy has been to identify therapies, hopefully FDA-approved drugs or investigational new drugs ( IND). that might be used in off-label applications to treat viral encephalitis after the virus has infected the brain. Data indicates that humanized monoclonal antibody or neuroprotective agents can treat rodents after West Nile virus has infected neurons in the brain. The objective of this project is to identify biochemical, viral or cellular markers in the cerebrospinal fluid (CSF) or serum for benchmark pathological events in live animals that are needed for a) effectively treating viral encephalitis, b) determining the order and timing of these pathological events, c) clinically managing the treatment, and d) planning clinical trials. Additionally, the objective is to use these markers to appropriately treat West Nile virus (WNV) encephalitis, Venezualen encephalitis (VEE) and Western equine encephalitis (WEE) using hopefully FDA-approved drugs or IND.
Specific Aim #1: Identify and correlate post-mortem markers with time-course of disease using viral expression, immunohistochemistry, blood-brain-barrier (BBB) permeabilization, necrosis, neuron apoptosis or neuro-inflammation in specific portions of the brain.
Specific Aim #2: Antemortem markers will be identified in CSF of uninfected and virally infected hamsters using viral and/or immunological assays, and 2-D gel electrophoresis fluorescent-labeled protein technology (DIGE) coupled with mass spectrophotometry.
Specific Aim #3: Use CSF or serum markers to identify, and most effectively administer, therapies for WNV, WEE or VEE disease. Therapeutics will be evaluated in the hamster or mouse models at different stages of disease using clinical or CSF/serum markers and will be administered in the brain by convection-enhanced delivery (CED) or peripherally.
Project interactions:We are collaborating with the aerosolization animal facility (CSU) to evaluate therapies of WNV-aerosolized rodents, and the preclinical development core (U of U) to evaluate humanized monoclonal antibody.