# Project 3: TRiC modulation of CNS pathogenesis in HD mouse models

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $301,377

## Abstract

Project Summary/Abstract
Biochemical analysis and cell based phenotypic assays clearly establish the impact of modulation of the TRiC
chaperonin system on mutant Huntingtin protein. To develop an effective TRiC based therapeutic strategy for
blunting the pathological impact of mutant HTT, it is essential that studies on TRiC chaperonin interactions with
mutant HTT be carried out in an animal model setting as close as possible to the human brain. The studies
proposed in this project directly address this central issue. Aim 1: To perform an integrated evaluation of the
impact of apiCCT1 delivery to the mouse striatum on mutant HTT biochemistry and quantitative measures of
HD pathology. Preliminary data demonstrates that exogenous application of the apical domain of CCT1 in cells
is sufficient to modulate aberrant accumulation of mHTT. To form an accurate and quantitative understanding
of the impact of apiCCT1 delivery to CNS cells in vivo we will deliver apiCCT1 by several alternative modalities
and 1) carry out assessments of the status and levels of aberrant forms of expanded repeat containing HTT
including soluble, oligomeric and fibrillar forms, 2) assess the impact on HD pathological phenotypes in HD
mouse models, including using reporters for the measure of transcriptional dysregulation, an early,
characteristic HD phenotype, and 3) quantitatively assess the efficiency of uptake and subcellular localization
of delivered apiCCT1. Aim 2: Evaluate the impact of the modulation of additional components of the TRiC
system and TRiC inspired reagents on HD pathology and mutant HTT behavior in mouse brain. In projects 1
and 2 of this proposal, novel TRiC based or TRiC inspired reagents including novel forms of apiCCT1
optimized for therapeutic benefit, other components of the TRiC chaperonin system such as CCT3 and CCT5
and combinations of TRiC inspired reagents, will be developed. In this project, these novel TRiC inspired
reagents will be tested in mouse brain for their impact on mutant HTT driven pathology and biochemistry using
methodologies used for apiCCT1 in specific aim 1. Aim 3: Bring an optimized TRiC based therapeutic strategy
to full scale behavioral testing and evaluation of neuronal trafficking in HD model mice to evaluate the potential
clinical utility of this strategy. We will carry out full scale behavioral testing in fragment (R6/2) and full length
(BACHD) HD model mice of optimized TRiC chaperonin based therapeutic intervention for HD. These studies
will be designed to serve as initial preclinical studies to evaluate TRiC chaperonin therapy for human use. We
will use neuronal trafficking assays based on studies already shown to demonstrate the striking impact of TRiC
chaperonin activity in cell culture to assess the impact of TRiC chaperonin therapy on this significant parameter
of neuronal health and function on full length HD model mice in vivo.

## Key facts

- **NIH application ID:** 9936263
- **Project number:** 5P01NS092525-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Leslie Michels Thompson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $301,377
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936263

## Citation

> US National Institutes of Health, RePORTER application 9936263, Project 3: TRiC modulation of CNS pathogenesis in HD mouse models (5P01NS092525-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9936263. Licensed CC0.

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