# miR-17~92 Haploinsufficiency Influences Alveolar and Vascular Endothelial Development

> **NIH NIH K08** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2021 · $163,080

## Abstract

PROJECT SUMMARY
This application is for a mentored research and career development program that will enable a motived junior
physician-scientist to develop the skills necessary to ultimately become an independent investigator.
Successful completion of this project will enable the investigator to gain the sills and knowledge necessary to
launch a career investigating the mechanisms responsible for the lung damage present in bronchpulmonary
dysplasia (BPD) and potentially develop targeted therapeutics to reverse or cure this damage. BPD is a lung
disease that affects more than 14,000 premature infants each year with prolonged health ramifications that
affect lung function throughout the patient's life. No curative therapies currently exist for BPD. In previous work,
we have shown that epigenetic silencing of a cluster of microRNAs, called miR-17~92, is associated with
severe BPD in human patients and murine models of the disease. In order to establish a causal relationship
between altered miR-17~92 expression and a BPD phenotype, this project will investigate the central
hypothesis that: murine genetic partial-deletion (or haploinsufficiency) of the miR-17~92 cluster will alter
alveolar and vascular development reminiscent of a BPD phenotype via exaggerated TGF-β, collagen and
matrix metalloproteinase expression. In Aim 1, in vivo and in vitro systems will be used to determine the effects
of miR-17~92 haploinsufficiency on pulmonary epithelial development and function. A causal relationship will
be determined by reintroduction of miR-17~92 using a viral vector to establish return of function and
phenotype. Since there is significant cellular cross-talk driving alveolar and vascular endothelial development,
Aim 2 will quantify the effects of haploinsufficiency on pulmonary vascular endothelial development and
function. Similar to Aim 1, a causal mechanism will be established with return of function experiments by
reintroduction of the full expression of miR-17~92 by viral vector. This novel study will impact the field through
understanding the cellular mechanisms altered by suppression and subsequent restoration of the miR-17~92
cluster. Furthermore, this study is significant because it provides a model to investigate the cellular
mechanisms responsible for alveolar and vascular endothelial simplification that occurs in traditional BPD
models without the confounding free-radical damage caused by high oxygen exposure. The above outlined
aims will be investigated in an environment with an established history of successful mentorship of junior
faculty to independence. Under the supervision of an expert advisory committee, the applicant will 1) Advance
her technical skills, with acquisition of as murine pulmonary function testing, immunohistochemistry, and next
generation sequencing techniques; 2) Learn advanced biostatistics; and 3) Learn delivery mechanisms of
targeted therapeutics. Future independent studies will likely focus on the developmental int...

## Key facts

- **NIH application ID:** 10063017
- **Project number:** 5K08HL140152-04
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Mary E Robbins
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,080
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063017

## Citation

> US National Institutes of Health, RePORTER application 10063017, miR-17~92 Haploinsufficiency Influences Alveolar and Vascular Endothelial Development (5K08HL140152-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10063017. Licensed CC0.

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