# TRiP resources for modeling human disease

> **NIH NIH R24** · HARVARD MEDICAL SCHOOL · 2022 · $316,391

## Abstract

Project Summary / Abstract
This application requests supplemental funding for our parent grant, R24 OD030002 “TRiP resources for
modeling human disease.”
Genetics play a pivotal role in Alzheimer’s disease (AD), with heritability estimates of 56–79% for common
forms of late-onset AD and over 90% for rarer forms of early-onset AD. Early findings pointed to mutations in
the amyloid precursor protein gene (APP) and presenilin genes, and subsequent genetic research has now
identified >50 other AD susceptibility loci that potentially contribute to disease etiology. Frontotemporal
dementia (FTD) is among the most common Alzheimer’s disease related dementias in people under 60, and
like AD, also has a strong genetic component. Linkage studies and GWAS have identified FTD associated
mutations in C9orf72, MAPT, and GRN, and several other potential risk loci. While many mutations are in gene
regulatory regions, a significant number of coding sequence variants have been implicated as AD and FTD risk
factors. For most of these variants it is unknown how they trigger neurodegeneration and their effect in
combination with each other. With its powerful genetic tools, and well-established AD and FTD models, the fly
presents an opportunity to systematically study how these protein-altering mutations, identified from human
patients, influence disease progression. In this supplement request, we propose to extend our resource to
model in vivo 100 variants identified in human AD and FTD gene coding sequence by using CRISPR to target
and alter the conserved amino acids in the fly orthologs. Unlike most fly studies on AD and FTD, which have
used randomly generated loss-of-function mutations, this new resource will facilitate Drosophila research of
specific phenotypes caused by the loss or change in a single amino acid in the endogenous protein, genetic
interactions between risk factors, and allow for screens for additional enhancers and suppressors of mutant
phenotypes. To increase the value of the resource to the community, we will first determine the viability and
neurodegeneration phenotypes associated with the mutant flies, including assays for locomotion defects, brain
histology, and caspase activation. Then we will analyze of the effect of the AD and FTD mutants on well-
established Drosophila models of toxicity caused by tau and C9ORF72 repeat expansion.

## Key facts

- **NIH application ID:** 10496279
- **Project number:** 3R24OD030002-03S1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** NORBERT PERRIMON
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $316,391
- **Award type:** 3
- **Project period:** 2020-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496279

## Citation

> US National Institutes of Health, RePORTER application 10496279, TRiP resources for modeling human disease (3R24OD030002-03S1). Retrieved via AI Analytics 2026-07-19 from https://api.ai-analytics.org/grant/nih/10496279. Licensed CC0.

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