# Disease Model Development and Phenotyping Project

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $2,255,991

## Abstract

ABSTRACT
 The goal of the Disease Model Development and Phenotyping Project (DMDPP) is to produce and
characterize the next generation of animal models for AD that accurately model the pathology of late onset AD
(LOAD) and to provide predictive models for therapeutic development. These models will be generated under
transparent and open intellectual property conditions. The Jackson Laboratory will conduct 2nd-site validation
of LOAD models and will ensure their broad availability and rapid dissemination to all researchers. The
foundation of this endeavor is our innovative APP knock-in (APP-KI) mouse that expresses humanized Aß at
physiological levels, and which exhibits amyloid plaque deposition (see introduction). We will complete our
base platform for development of mouse models of LOAD, by humanizing the mouse Tau (Mapt) locus by
replacing coding exons of mouse Tau with those from the human Tau (MAPT) locus. To double homozygous
APP-KI and hTau (APP-KI+/+/hTau+/+) mice, we will add the major risk factor for LOAD, APOE4. To expedite
analysis of additional factors influencing LOAD, the DMDPP will make extensive use of CRISPR/Cas9
technology to generate animal models that express polymorphisms in risk factors identified from genome wide
association studies (GWAS), including TREM2, PICALM, BIN1, CD2AP, ABCA7 and EPHA1. The effect of
each GWAS allele in generating a LOAD phenotype will be determined when combined with APP-KI, and
hTau. Subsequently we will combine specific GWAS alleles to investigate for synergistic effects on LOAD
pathology. The incorporation of multiple GWAS polymorphisms on the APP-KI+/+/hTau+/+ background and
production of cohorts of mice for analysis will be accelerated using IVF and embryo transfer instead of
standard breeding.
 The molecular pathological phenotypes in these LOAD models will be characterized at an
unprecedented level of detail through a novel and innovative immunological approach, using conformation
dependent and aggregation specific monoclonal antibodies that distinguish eight different types of amyloid
deposits in humans and transgenic mice. The molecular phenotype will also be comprehensively determined
by quantifying neurons and microglia, synaptic loss, soluble and insoluble tau and Aß and markers of phospho
tau. The core will also characterize the gene expression profile of the models by RNAseq and epigenetic
markers, as well as structural, functional, and diffusion magnetic resonance imaging. The behavioral
phenotype will be characterized by elevated maze, open field, and novel object recognition. The extensive data
generated will be used to compare the molecular pathology to that of LOAD and to decide which lines to
advance for further development and testing to produce the next generation of animal models.

## Key facts

- **NIH application ID:** 10003930
- **Project number:** 5U54AG054349-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** GRANT R MACGREGOR
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,255,991
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003930

## Citation

> US National Institutes of Health, RePORTER application 10003930, Disease Model Development and Phenotyping Project (5U54AG054349-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003930. Licensed CC0.

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