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Cellular Senescence as a New Mechanism of Bronchopulmonary Dysplasia (BPD)

Award Number: R56HL149733
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Cellular Senescence as a New Mechanism of Bronchopulmonary Dysplasia (BPD) - ABSTRACT: Bronchopulmonary dysplasia (BPD) has been linked to decreased lung epithelial cells proliferation, impaired alveolarization and arrest in lung development, the mechanism for these abnormalities in lung development are unknown. In recent work, we uncovered a novel mechanism for hyperoxia-mediated damage to pulmonary alveolarization, impaired lung development and function. We noted that moderate, clinically- relevant, hyperoxia (60% O2) induces cellular senescence in fetal lung type II alveolar epithelial cells (AECs) both in culture as well as in lungs of neonatal BPD mice. Mechanistically, we found that hyperoxia damaged mitochondrial and impaired clearance of nonfunctional/damaged mitochondrial by pink/parkin mediated mitophagy pathway is associated with induction of senescence in lungs of BPD mice. Based on these observations, we propose the following central hypothesis regarding the pathogenesis of BPD: prolonged pulmonary exposure to hyperoxia impairs mitophagy and induces cellular senescence in Type II AECs leading to decreased epithelial cell proliferation and differentiation, a required process for normal lung development. We postulate that attenuating cellular senescence by augmenting the mitophagy process (clears damaged/dysfunctional mitochondria) or removing senescent cells in BPD lungs will improve alveolarization and lung function. Our hypothesis will be tested in 3 Specific Aims. In Specific Aim 1, we will first determine the expression of senescence and SAPS markers in RA (control) and BPD lungs tissues. We will corroborate these finding in lung tissues and tracheal aspirates obtained from human neonates at various stage of BPD development. We will finally confirm the role of cellular senescence in abnormal alveolarization and decline lung function using global p21 knock out and lung Type II epithelial specific p21 knockout mice. In Specific Aim 2, we will establish the role of impaired mitophagy as a potential mechanism by which cellular senescence impairs lung alveolarization and compromises lung function in BPD. We will perform loss-of-function studies (using global pink1 and parkin knockout mice as well as lung epithelial cell specific parkin knockout mice) to determine whether mitophagy is required for attenuating senescence of AECs, improve pulmonary alveolarization, normal lung development and function. Lastly, in Specific Aim 3, we will evaluate the therapeutic utility of cellular senescence attenuation or selective removal of senescent cells to improve alveolarization and lung function. We will test: a) mTOR inhibitors (Sirolimus, also known as Rapamune and Torin1) to enhance removal of damaged/dysfunctional mitochondria by augmenting the mitophagy process and attenuating cellular senescence in the lung alveolar epithelium of BPD mice, b) whether senolytic drugs (DQ) that selectively remove senescent cells from the lungs will improve lung development and physiological function of BPD mice lungs. In summary, this proposal presents an innovative approach to understand the mechanism for hyperoxia-induced abnormal alveolarization and development of 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: 2025 ( Subtotal = $0 )
2025	2020	THE COOPER HEALTH SYSTEM, A NEW JERSEY NON-PROFIT CORPORATION	1 COOPER PLAZA	CAMDEN	NJ	08103	CAMDEN	USA	Lung Diseases Research	000	1	10/8/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	COOPER HEALTH SYSTEM, THE	1 COOPER PLAZA	CAMDEN	NJ	08103	CAMDEN	USA	Lung Diseases Research	000	1	9/2/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	COOPER HEALTH SYSTEM, THE	1 COOPER PLAZA	CAMDEN	NJ	08103	CAMDEN	USA	Lung Diseases Research	001	1	8/18/2021	NEW	$0
2021	2020	COOPER HEALTH SYSTEM, THE	1 COOPER PLAZA	CAMDEN	NJ	08103	CAMDEN	USA	Lung Diseases Research	000	1	12/12/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $342,500 )
2020	2020	COOPER HEALTH SYSTEM, THE	1 COOPER PLAZA	CAMDEN	NJ	08103	CAMDEN	USA	Lung Diseases Research	000	1	9/16/2020	NEW	$342,500
														Subtotal = $342,500

Grand Total All Awards = $342,500

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Cellular Senescence as a New Mechanism of Bronchopulmonary Dysplasia (BPD)

Award Number: R56HL149733

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/17/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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