# Development of a Conditional Inducible Huntington’s Disease Murine Model to Study Complex Pathogenic Mechanisms

> **NIH NIH R03** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $168,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10352824
- **Project number:** 1R03NS125224-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Mark F Mehler
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $168,000
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352824

## Citation

> US National Institutes of Health, RePORTER application 10352824, Development of a Conditional Inducible Huntington’s Disease Murine Model to Study Complex Pathogenic Mechanisms (1R03NS125224-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10352824. Licensed CC0.

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