# Analysis of environmentally-sensitive epigenetic machinery during osteogenic differentiation

> **NIH NIH R00** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $249,000

## Abstract

Every 4.5 minutes, a baby is born with a birth defect in the United States. Skeletal defects of the bony skeleton
have been associated with environmental chemical exposure in utero. Our lab has shown that proper
development of osteoblasts, the bone forming cells, depends on tight regulation of bone-specific genes. We
developed a human embryonic stem cell (hESC) system where toxicant-induced differential gene expression
perturbed osteoblast differentiation. MicroRNAs (miRNAs) are small non-coding RNAs that epigenetically
regulate gene expression and are actors of skeletal development. There is no knowledge whether miRNAs
adversely respond to environmental agents to result in skeletal malformations. In this proposal, I hypothesize
that toxicant-induced miRNA changes play a critical role in the manifestation of skeletal birth defects. MiRNA
profiling on differentiating hESCs previously identified 10 miRNAs downregulated stemming from chemical
exposure that repressed osteoblast differentiation. I propose to 1) validate the functional role of candidate
miRNAs during osteogenesis (K99); 2) investigate whether the functional effects of the candidate miRNAs are
replicated in vivo (K99); 3) determine the mRNA target genes and signaling pathways affected by the candidate
miRNAs (K99); and 4) investigate whether miRNA dysregulation is facilitated through epigenetic machinery that
represses miRNA expression (R00). The proposed aims will significantly impact the understanding of
environmentally induced epigenetic toxicity during skeletal development. Mentors Drs. Martin Riccomagno
(survival surgeries and genome engineering) and Nicole zur Nieden (hESCs, miRNAs and genome engineering)
will aid in my training for successful completion of the proposed aims and becoming an independent principal
investigator. Additional support will come from Drs. Martin Garcia-Castro (molecular cytogenetic techniques) and
Patrick Allard (epigenetic toxicology). The career development plan includes training to enhance my research
skills, including Next Generation Sequencing, bioinformatics, in utero electroporation, and in vivo skeletal
analysis, as well as scholarly skills and professional development, including but not limited to science
communication, writing, mentoring, and management skills. The planned training and research will facilitate the
transition to independency and success as a principal investigator.

## Key facts

- **NIH application ID:** 10695026
- **Project number:** 5R00ES032486-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Nicole Renee Sparks
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-12-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695026

## Citation

> US National Institutes of Health, RePORTER application 10695026, Analysis of environmentally-sensitive epigenetic machinery during osteogenic differentiation (5R00ES032486-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10695026. Licensed CC0.

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