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Remodeled airway irritant reflexes as a cause of serious cardiovascular events

Award Number: R01HL152219
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/26/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Remodeled airway irritant reflexes as a cause of serious cardiovascular events - Air pollutants/irritants evoke dangerous sympathoexcitatory reflexes in individuals with cardiovascular disease (CVD) but evoke sympathoinhibitory reflexes in healthy subjects. However, there is a major gap in understanding how irritant-evoked pulmonary-cardiac reflexes are remodeled in CVD. This is significant because it is the reflex remodeling that determines the impact of pollution and thus the fundamental cause of acute pollutant-evoked cardiovascular (CV) events, which are responsible for >100k US deaths annually. Thus, there are no clinical options to treat or identify at-risk individuals. Irritant inhalation triggers pulmonary-cardiac reflexes via the acti- vation of vagal airway afferent nerves that express transient receptor potential (TRP) ankyrin 1 and vanilloid 1. TRPs are typically expressed on C- but not A-fibers, which can trigger parasympathetic and sympathetic reflexes, respectively. The long-term goal is a complete understanding of the mechanisms and networks responsible for the aberrant pulmonary-cardiac reflexes in CVD. The objective here is to determine the specific afferent and efferent signaling evoked by airway TRP activation in two CVD rat models and determine the mechanistic cause of the CVD-linked reflex remodeling. The central hypothesis, based upon strong preliminary data, is that aberrant irritant-evoked pulmonary-cardiac reflexes in CVD are due to the de novo reflex recruitment of sympathetic ef- ferent nerves downstream of neurotrophin-dependent remodeling of TRP-expressing airway afferent networks. The hypothesis is innovative because this is the first time that the basis of the pathophysiology – the remodeling of pulmonary-cardiac reflexes – has been targeted. Aim 1: Identify the autonomic efferent pathways responsible for the remodeled airway irritant-evoked reflexes in CVD. We hypothesize that CVD switches irritant-evoked pulmonary-cardiac reflexes from parasympathetic-mediated bradycardia towards tachyarrhythmia due to de novo recruitment of cardiac sympathetic efferent nerves. Aim 2: Determine the airway afferent signaling required for the remodeled irritant-evoked pulmonary-cardiac reflexes in CVD. We hypothesize that irritant-evoked sym- pathoexcitation in CVD is due to de novo expression of TRPs in airway vagal A-fiber afferents. Aim 3: Determine the mechanism underlying the remodeling of pulmonary-cardiac reflexes in CVD. We hypothesize that remodel- ing of pulmonary-cardiac reflexes in CVD is dependent on vagal afferent neurotrophin TrkB receptor activation downstream of chronic activation of the renin-angiotensin system (RAS). All aims are supported by preliminary data. This study is significant because it will provide the rationale for pharmacological (e.g. RAS inhibition, TrkB inhibition, nasal menthol) and electroceutical therapies to reduce the impact of remodeling or reverse the remod- eling in clinical studies. Our innovative approach will target unique nociceptive subsets and mechanisms in an- esthetic-free conditions using state-of-the-art electrophysiological techniques. Thus, these studies will have a transformative impact upon our understanding of irritant-evoked reflexes in CVD, and are expected to lead to a substantive shift in our approach to reduce the impact of pollutants/irritants on susceptible populations.


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 = $518,089 )
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	4	12/14/2023	NON-COMPETING CONTINUATION	$475,796
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	001	4	6/19/2024	NON-COMPETING CONTINUATION	$42,293
														Subtotal = $518,089

Issue Date FY: 2023 ( Subtotal = $528,663 )
2023	2023	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	3	1/19/2023	NON-COMPETING CONTINUATION	$475,796
2023	2023	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	001	3	3/6/2023	NON-COMPETING CONTINUATION	$52,867
														Subtotal = $528,663

Issue Date FY: 2022 ( Subtotal = $528,663 )
2022	2022	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	2	12/15/2021	NON-COMPETING CONTINUATION	$475,796
2022	2022	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	001	2	6/15/2022	NON-COMPETING CONTINUATION	$52,867
														Subtotal = $528,663

Issue Date FY: 2021 ( Subtotal = $541,038 )
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	001	1	6/14/2021	NEW	$54,104
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	1	1/26/2021	NEW	$486,934
														Subtotal = $541,038

Grand Total All Awards = $2,116,453

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Remodeled airway irritant reflexes as a cause of serious cardiovascular events

Award Number: R01HL152219

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/26/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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