# Skeletal Phenotyping of Heterozygotes from IMPC Embryonic Lethal Lines

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $584,901

## Abstract

Abstract
The International Mouse Phenotyping Consortium (IMPC) has developed an invaluable repository of gene
knockout (KO) mice and has performed a whole-animal assessment of each KO line. Approximately 1/3 of the
KO lines are embryonic lethals that were characterized as heterozygous (HET) KO lines. Previously we
performed high throughput µCT and histomorphometric analysis on 220 unselected viable homozygous (HOM)
KO lines. This study found that ~12.5% have an unequivocal variance in total bone mass (trabecular bone
volume and/or bone size), most of which were not detected by the IMPC screening. The results and
interpretation of the KOs examined in the screen are available on a web portal (bonebase.org). Based on this
experience, the phenotyping data on the IMPC webportal and the literature, we estimate that the HET
population of KOs will be an equally rich source of genes that affect bone/body variance and skeletal health in
the later adult years. This proposal will apply our skeletal phenotyping workflow to selected HET KO lines that
are likely to have a significant bone/body mass phenotype. Both µCT and total body composition as
determined by TD-NMR will be used as the screening modality. HET KO lines with significant variance in bone
architecture will be processed for histomorphometry. Based on those results, certain lines will undergo studies
of osteogenesis (Raman microscopy for the mineral/matrix composition, primary cell culture for osteoblast)
and/or osteoclastogenesis (collagen crosslinks and primary cell culture for osteoclast). In HET KO lines with
variance in body composition, histomorphometry of the skeletal muscle will be performed. The intent is to
discriminate the impact of the HET KO as acting directly on the osteoblast or osteoclast, or whether the
observed phenotype is a secondary effect of the HET KO on other tissues that can influence bone. In addition,
HOM KO lethal lines that survive to 18.5 days of gestation will undergo a gross and histological skeletal
examination to determine the impact of the gene on skeletal development. To complement these biological
findings, a bioinformatics component is being added to map the KO genes that are affecting osteoblast or
osteoclast directly to known or postulated molecular pathways. Does the gene participate in the function of the
network or is it a product of a network? The final goal of the project is to place the biological and bioinformatic
data into a classification structure that reveals differences and similarities between the various KO lines. We
will engage internal and external experts in bone biology to review the data assembled for a specific HET KO
line to critique and amplify our interpretation and ever-evolving classification schema. Recognizing that
frequency and complexity of the genes affecting bone is a big-data challenge (estimated to be ~3,500 genes),
our intent is to lay the ground work for how this information will be gathered, presented, interpreted, queried
...

## Key facts

- **NIH application ID:** 9905541
- **Project number:** 5R01HD098636-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** PETER MAYE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $584,901
- **Award type:** 5
- **Project period:** 2019-04-02 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905541

## Citation

> US National Institutes of Health, RePORTER application 9905541, Skeletal Phenotyping of Heterozygotes from IMPC Embryonic Lethal Lines (5R01HD098636-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9905541. Licensed CC0.

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