Huntington?s disease (HD) is caused by a single gene defect consisting of an aberrant trinucleotide repeat expansion in Huntingtin (HTT). This genetic defect gives rise to a broad array of pathophysiological alterations leading to a multi-system disease whose most characteristic traits are those resulting from its neurological alterations: neuropsychiatric disorders, motor deficits and striatal degeneration. However, no less important are those disease traits resulting from impairments affecting other organ, tissue and cellular systems, including aberrant inflammatory responses, skeletal muscle dysfunction, metabolic alterations, and liver dysfunction. Given this systemic involvement, these impairments likely synergize with neurological deficits, further altering their disease course. To further complicate the study of HD pathogenesis, recent investigations have shown that pathogenic alterations also result from asynchronous events taking place during early neural development, postnatal maturation as well as throughout adult life. This complex interplay, involving multiple cellular alterations, time-dependent processes and their concerted interactions, has made it particularly challenging to elucidate primary mechanistic events and processes and, as a corollary, to promote the design of precision medicine interventions. To effectively dissect specific primary pathophysiological mechanisms, it is necessary to employ a genetic tool with the ability to conditionally induce the full-length mutant gene in HD-targeted cells at the relevant times and places underlying disease pathogenesis. To accomplish this goal, we have created a novel genetic model whose expression of the human full-length mutant HTT transgene is abrogated by the presence of a loxP floxed STOP cassette within HTT intron 1, the iBACHD strain. The overall goal of this R03 application is to genetically characterize the iBACHD strain, and to validate its use for better modeling of HD in vivo. The characterization and validation of the iBACHD model will be achieved through three Specific Aims: (1) the characterization of transgene integration in term of copy number and genomic location; (2) the characterization of STOP cassette functional integrity and the pattern of expression of mutant human HTT after excisional recombination of the STOP cassette; and (3) ability of the iBACHD model to recapitulate the main hallmarks of HD: neuropsychiatric abnormalities, motoric deficits and striatal degeneration. These studies are significant as they will fill a critical gap in our experimental arsenal to dissect individual mechanisms of a multi- system disorder. Our studies will yield a highly innovative tool that would result in a departure from the status quo of mechanistic studies based on mouse models with less versatile expression of the pathogenic gene and protein product.
|Effective start/end date||9/1/21 → 2/28/23|
- National Institute of Neurological Disorders and Stroke: $168,000.00
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