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Exosomal Gasdermin D Mediated Lung to Brain Crosswalk in Preterm Brain Injury

Award Number: R01HL156803
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Exosomal Gasdermin D Mediated Lung to Brain Crosswalk in Preterm Brain Injury - PROJECT SUMMARY Bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development is the most common morbidity complicating preterm birth, and a predictor of poor neurodevelopmental outcomes. Currently it is unclear to what extent lung injury contributes to neurodevelopmental impairment (NDI) in these preterm infants. Based on our preliminary data which demonstrate that circulating exosomes derived from preterm infants who develop severe BPD induce neural stem cell (NSC) death in vitro, the major goal of this proposal is to determine the molecular mechanisms by which these circulating exosomes mediate lung to brain crosstalk and their contribution to brain injury and NDI. Understanding these mechanisms is fundamental to public health as more preterm infants are surviving, yet there remains no effective therapy for either BPD or its associated NDI. Pyroptosis is a newly described form of inflammatory cell death that is solely regulated by gasdermin D (GSDMD), an inflammasome-activated membrane “pore-forming” protein. Exosomes are nano- sized extracellular vesicles that play a key role in inter-organ communications. We recently demonstrated that preterm infants who develop severe BPD have increased expression of GSDMD and surfactant protein C (SPC), a marker of alveolar type II epithelial cells (AEC), in their circulating exosomes at 1 week of age. In preclinical studies with an experimental model of BPD, similar GSDMD-containing exosomes were isolated from the serum of newborn rats exposed to hyperoxia. Importantly, adoptive transfer of these exosomes into the circulation of normal newborn rats impaired brain development. These findings lead us to propose a novel model that links BPD, exosomal GSDMD and brain injury. The central hypothesis of this model is that GSDMD-containing exosomes are released from AEC into the circulation during the evolving stage of BPD, and neuronal uptake of these exosomes results in neural cell pyroptosis and NDI. This hypothesis will be tested through three aims: Aim 1. To characterize the relationship between GSDMD expression profiles in AEC-derived circulating exosomes and the severity of BPD in preterm infants. Aim 2. To determine the mechanistic functions of circulating exosomes from preterm infants in inducing brain injury and NDI. Aim 3. To elucidate the molecular mechanisms by which hyperoxia stimulates AEC to release GSDMD+ exosomes that induce brain injury and NDI. These studies will delineate a novel exosomal GSDMD-mediated lung to brain crosstalk that is critical in the pathogenesis of brain injury and NDI in premature infants. Completion of this project will provide a strong foundation to further explore therapeutic interventions that target exosomal GSDMD to improve long-term respiratory and neurodevelopment outcomes in these infants. This proposal is aligned with the overarching goal of the NICHD and NHLBI that is to improve children’s health through cutting edge research and it will be executed by a team approach with experts in clinical and basic respiratory research, neuropathology, and exosome and GSDMD biology.


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: 2026 ( Subtotal = $0 )
2026	2023	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Lung Diseases Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $563,039 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Lung Diseases Research	000	4	7/14/2023	NON-COMPETING CONTINUATION	$457,511
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Lung Diseases Research	001	4	8/26/2023	SUPPLEMENT FOR EXPANSION	$105,528
														Subtotal = $563,039

Issue Date FY: 2022 ( Subtotal = $483,281 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Lung Diseases Research	000	3	6/24/2022	NON-COMPETING CONTINUATION	$483,281
														Subtotal = $483,281

Issue Date FY: 2021 ( Subtotal = $892,647 )
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Lung Diseases Research	001	2	6/11/2021	SUPPLEMENT FOR EXPANSION	$383,750
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Lung Diseases Research	000	2	6/8/2021	NON-COMPETING CONTINUATION	$508,897
														Subtotal = $892,647

Issue Date FY: 2020 ( Subtotal = $456,220 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Lung Diseases Research	000	1	8/5/2020	NEW	$456,220
														Subtotal = $456,220

Grand Total All Awards = $2,395,187

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Exosomal Gasdermin D Mediated Lung to Brain Crosswalk in Preterm Brain Injury

Award Number: R01HL156803

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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