# Leadership Implementation Project

> **NIH NIH U54** · WASHINGTON UNIVERSITY · 2020 · $36,448

## Abstract

Leadership/Implementation Project
Project Summary
This application proposes the Washington University in St. Louis School of Medicine (WUSM) Model Organism
Screening Core (wuMOSC) as a key asset for Phase II of the NIH Undiagnosed Diseases Network (UDN). The
wuMOSC will evaluate the pathogenicity of 200 genetic variants per year identified by UDN Clinical Sites in
otherwise undiagnosed participants by leveraging the optimal combination of the following four model organism
and cell-based Resource Cores: 1) C. elegans, 2) Drosophila, 3) zebrafish, and 4) human pluripotent stem
cells (hPSCs). The combination of these model systems allows for extremely rapid and cost-effective variant
evaluation in C. elegans, and evaluation in hPSCs of genes and variants that are not conserved in the animal
model organisms, while maintaining the established advantages of the Drosophila and zebrafish models. An
experienced Leadership Team has been assembled that harnesses the collaborative research environment at
WUSM, including the expertise of the McDonnell Genome Institute, and the superb WUSM clinical partners
that constitute the proposed UDN Phase II WUSM Sequencing Center and Clinical Site applications,
respectively. Using proven, cutting-edge, and novel bioinformatic approaches, combined with thoughtful
consideration of the advantages and limitations of each model organism, a careful assessment plan has been
defined for determining the putative pathogenicity of nominated variants and prioritizing them for further
evaluation by the Resource Cores. The leaders of the four Research Cores have significant expertise in the
relevant model system, and are currently employing the proposed advanced genetic approaches
(CRISPR/Cas9 knock-in, tissue-specific RNAi and overexpression, and testing variant mRNA for null mutant
rescue) and extensive phenotypic analysis to assess human gene variants for effect on gene product function.
The UDN Clinical Sites, Steering Committee, and Coordinating Committee will receive frequent
communications regarding plans and results of the wuMOSC, through the activity of the Administrative Core,
which will also disseminate acquired model organism expertise to the wider NIH and other research
communities. Therefore, the wuMOSC will have an exceptionally high impact on the diagnostic efforts of the
UDN by bioinformatically and experimentally screening potential disease-causing variants in the context of
disease-specific phenotypes.

## Key facts

- **NIH application ID:** 9968486
- **Project number:** 5U54NS108251-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** TIM SCHEDL
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,448
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968486

## Citation

> US National Institutes of Health, RePORTER application 9968486, Leadership Implementation Project (5U54NS108251-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9968486. Licensed CC0.

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