Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 5e. TASK NUMBER 5f. WORK UNIT NUMBER
REPORT DATE
PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERRosalind Franklin University of Medicine and Science North Chicago, IL 60064
SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)
U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012
SPONSOR/MONITOR'S REPORT NUMBER(S)
DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited
SUPPLEMENTARY NOTESOriginal contains colored plates: ALL DTIC reproductions will be in black and white.
ABSTRACTPurpose: Alternative splicing is responsible for producing several products from a single transcript and can cause pathogenic changes in RNA in neurodegenerative disease. This proposal tests the hypothesis that regulation of normal splicing is disrupted in Parkinson's disease (PD). Scope: Experiments are designed to determine splicing products in the brain and blood of experimental MPTP models of PD and the blood of newly diagnosed PD patients, who are not yet on dopamine therapy. The overall goal is to use splice variants as biomarkers to identify individuals at risk for PD. To date, we have identified and quantified alternatively spliced transcripts for several candidate genes in MPTP models of PD. We have also obtained IRB permission to study splicing factors in the blood of newly diagnosed PD patients. Major Findings: Mice treated chronically with MPTP show a shift in the ratio of FosB, RGS9 and Ania6 splice variants in the striatum, 3 days post-treatment. The splicing ratios for AChE and Ania 6 also change in the blood following chronic treatment and, for Ania 6, the changed ratio persists up to 3 weeks after treatment. Progress in the first year includes 4 abstracts, a peer-reviewed publication and an article in preparation.
SUBJECT TERMS
Appendices……………………………………………………………………………16
INTRODUCTIONAn important pathological hallmark of Parkinson's disease is the progressive and selective loss of nigrostriatal dopamine (DA) neurons. The mechanisms underlying the development and progression of this disease i...