# Translating Human Height Genetics to Skeletal Biology by Functional Genomics of the Growth Plate

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2022 · $173,340

## Abstract

Project Summary
Disorders of growth plate chondrocyte maturation impact the growth of the skeleton, resulting in a spectrum of
diseases from skeletal dysplasia to extreme short stature. These diverse conditions underscore the importance
of the tightly regulated chondrocyte life cycle to normal epiphysial physiology, yet the genetic pathways
directing chondrocyte maturation are poorly understood. The current proposal leverages an in vitro model of
the growth plate to (1) conduct high-throughput, genome-wide functional knock-out (KO) screening of
chondrocyte maturation, (2) prioritize screening hits with orthologues linked to human skeletal growth through
genome-wide association studies (GWAS), and (3) investigate the mechanisms by which top targets act to
affect chondrocyte maturation, beginning with top screening hit, Protein Inhibitor of Activated STAT1 (PIAS1).
As preliminary data for the current proposal, I developed a screening assay in which a lentiviral library of
80,000 unique single-guide RNAs (sgRNAs) is transduced into Cas9+ chondrocytes to simultaneously KO
20,000 genes in replicate. This assay can robustly detect genetic determinants of chondrocyte maturation and
has already identified genes highly relevant to skeletal biology, including members of the Indian hedgehog
signaling family. In the present application, I intend to uncover new genetic determinants of chondrocyte
maturation in the growth plate by adapting my preliminary screen to probe KOs leading to both delayed and
early chondrocyte maturity and intersect these results with GWAS data from human limb length. Furthermore, I
will investigate my hypothesis that PIAS1 acts to delay chondrocyte maturation through its regulation of
chondrocyte transcription and protein SUMOylation, while establishing a pipeline for future mechanistic studies
of top screening targets. Functional genomic screening can expedite discovery of new roles for genes
previously unstudied in human growth plate chondrocytes. By identifying new functional genetic mediators of
growth plate maturation, I hope to gain insight into the development of skeletal dysplasia and growth disorders
while establishing targets for the design of future therapeutics.

## Key facts

- **NIH application ID:** 10411894
- **Project number:** 5K08AR078370-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Nora Edwards Renthal
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $173,340
- **Award type:** 5
- **Project period:** 2021-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411894

## Citation

> US National Institutes of Health, RePORTER application 10411894, Translating Human Height Genetics to Skeletal Biology by Functional Genomics of the Growth Plate (5K08AR078370-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10411894. Licensed CC0.

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