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

Award Number: K08HL140152
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/15/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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miR-17~92 Haploinsufficiency Influences Alveolar and Vascular Endothelial Development - 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 interplay between the alveoli and vascular endothelium, and use of the miR-17~92 cluster as a biomarker and/or therapeutic target for BPD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	5	12/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $163,080 )
2022	2022	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	5	11/16/2021	NON-COMPETING CONTINUATION	$163,080
														Subtotal = $163,080

Issue Date FY: 2021 ( Subtotal = $163,080 )
2021	2021	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	4	12/1/2020	NON-COMPETING CONTINUATION	$163,080
														Subtotal = $163,080

Issue Date FY: 2020 ( Subtotal = $163,080 )
2020	2020	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	3	11/26/2019	NON-COMPETING CONTINUATION	$163,080
														Subtotal = $163,080

Issue Date FY: 2019 ( Subtotal = $162,840 )
2019	2019	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	2	12/20/2018	NON-COMPETING CONTINUATION	$162,840
														Subtotal = $162,840

Issue Date FY: 2018 ( Subtotal = $164,840 )
2018	2018	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	1	12/13/2017	NEW	$164,840
														Subtotal = $164,840

Grand Total All Awards = $816,920

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

Award Number: K08HL140152

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/15/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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