Increasing evidence suggests that transcriptional dysregulation in Huntington's disease (HD) perturbs cellular function and compromises protective mechanisms ultimately leading to neuronal death. We have discovered novel interactions between the Huntington's disease protein (huntingtin) and transcriptional regulators and that medications acting on these regulators are highly effective in vitro and in vivo. These compounds have provided by far the largest single drug effects on ameliorating the phenotype of HD transgenic mice to date. This work has arisen from collaborations between our different laboratories and the proposed projects are designed to understand and explore the therapeutic potential in lid of these compounds, conventionally used as chemotherapeutic agents. Project 1 (Dimitri Krainc, PI) will explore the molecular interactions between hunting(in and transcriptional machinery and how these interactions might be affected by medications. Project II (Dr. Rajiv Ratan, PI) will study the downstream mechanisms of neuroprotection exerted by the medications as they relate to oxidative and apoptotic signaling. Project IlI (Dr. Robert Fen'ante, PI) will utilize HD transgenic mice to examine the effects of the chemotherapeutic medications on an in vivo HD phenotype and model Preclinical treatments that can be used in humans. Project IV (Dr. Jang-Ho Cha, PI) will examine the effects of huntingtin and the medications on chromatin remodeling in part utilizing cells and tissues from the other aims. Project V (Dr. Steven Hersch, PI) will perform early phase clinical trials of the medications in HD patients to pave the way for potential large-scale efficacy trials. The Gene Expression Core (Dr. Ruth Luthi-Carter, PI) will provide transcriptional readouts relevant for studies in each of the projects. Our program thus examines new classes of therapeutic agents for HD and encompasses molecular, genetic and cellular mechanisms, therapeutic discovery in transgenic mouse models, and translation to early clinical use in HD patients. The projects are highly integrated, each interacting extensively with all the others to contribute to the overall program. The three institutions involved insure that the program will exist in a highly supportive environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
3P01NS045242-01S1
Application #
6802106
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Oliver, Eugene J
Project Start
2003-04-15
Project End
2008-03-31
Budget Start
2003-04-15
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$72,375
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Tourette, Cendrine; Farina, Francesca; Vazquez-Manrique, Rafael P et al. (2014) The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS Biol 12:e1001895
McFarland, Karen N; Das, Sudeshna; Sun, Ting Ting et al. (2013) Genome-wide increase in histone H2A ubiquitylation in a mouse model of Huntington's disease. J Huntingtons Dis 2:263-77
Taylor, David M; Moser, Roger; Regulier, Etienne et al. (2013) MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition. J Neurosci 33:2313-25
McFarland, Karen N; Das, Sudeshna; Sun, Ting Ting et al. (2012) Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease. PLoS One 7:e41423
Sleiman, Sama F; Langley, Brett C; Basso, Manuela et al. (2011) Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. J Neurosci 31:6858-70
Hu, Yi; Chopra, Vanita; Chopra, Raman et al. (2011) Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse. Proc Natl Acad Sci U S A 108:17141-6
Ebbel, Erika N; Leymarie, Nancy; Schiavo, Susan et al. (2010) Identification of phenylbutyrate-generated metabolites in Huntington disease patients using parallel liquid chromatography/electrochemical array/mass spectrometry and off-line tandem mass spectrometry. Anal Biochem 399:152-61
Zucker, Birgit; Kama, Jibrin A; Kuhn, Alexandre et al. (2010) Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease. J Neuropathol Exp Neurol 69:880-95
Benn, Caroline L; Luthi-Carter, Ruth; Kuhn, Alexandre et al. (2010) Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease. J Neuropathol Exp Neurol 69:817-27
Kim, Jinho; Amante, Daniel J; Moody, Jennifer P et al. (2010) Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease. Biochim Biophys Acta 1802:673-81

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