# Matched sets of full human gene-replacement mouse lines for MODEL-AD

> **NIH NIH R56** · UNIVERSITY OF MINNESOTA · 2021 · $1,329,167

## Abstract

We are responding to NOT-AG-18-049 “Collaborative Studies on AD/ADRD” by establishing a collaborative effort to
significantly expand the modeling capacity of the MODEL-AD Center. MODEL-AD was established by the NIA to
create, rigorously characterize and ensure the rapid distribution of the next generation of animal models of Late
Onset AD. Critical barriers to progress in making these next generation models are technique limitations that have
put restrictions on the size of the human genomic context incorporated into each of the new modified alleles in the
MODEL-AD mouse lines. Our group at the University of Minnesota (UMN) has developed Gene Replacement (GR)
technologies that allow us to routinely replace mouse genes with their full human orthologs up to several hundred kb
in size. We used this technology to generate a matched set of Microtubule Associated Protein Tau Gene-
Replacement (MAPT-GR) lines of mice in which we replaced the full mouse Mapt genomic coding and regulatory
region (156,547bp) with full human MAPT genomic sequences (190,081bp). We have confirmed that mice
homozygous for this MAPT-GR allele express human tau at endogenous levels, and that all expected splice variants
are found in the appropriate tissues and in ratios expected for the fully functional human MAPT gene. This model set
now includes two wt control lines (H1 or H2 MAPT haplotype) and a growing number of experimental lines that
precisely match the H1 wt control line except for the pathogenic variant that we specifically introduce into that
haplotype. The first of these lines are currently being further characterized by MODEL-AD and are now available to
the AD research community without restriction (JAX). Our specific aims for this collaboration are to: 1. Generate
Gene-Replacement (GR) sets of mouse lines in which genes involved in the etiology of AD have been
replaced by their full human homologs. We are proposing to develop 10 model sets for this collaboration (>20
total lines). 2. Characterize matched sets of GR lines using the established MODEL-AD methods and
distribute without restriction. The most translationally relevant alleles will be incorporated into the current
MODEL-AD “base model”. These GR lines will allow us and other AD researchers to evaluate the molecular impact
of pathogenic mutations and risk variants within the context of the full human gene sequence in which they occur in
patients. These mouse lines will contain all potential human therapeutic targets for each gene, ranging from the full
genomic DNA sequences to all RNA transcription and protein products that they encode. Because the genomic
sequences of these matched sets will differ only at sequences specifically changed in each line, any significant
molecular differences between these lines can confidently be attributed to the risk variant in the experimental lines,
and any therapeutic agents found to effectively correct these dysfunctions could be expected to have direct
therapeutic value ...

## Key facts

- **NIH application ID:** 10468368
- **Project number:** 1R56AG067573-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** MICHAEL D KOOB
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,329,167
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468368

## Citation

> US National Institutes of Health, RePORTER application 10468368, Matched sets of full human gene-replacement mouse lines for MODEL-AD (1R56AG067573-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10468368. Licensed CC0.

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