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Unravelling lung interoception and its functional consequence in the developing ovine lung

Award Number: R01AT011691
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Unravelling lung interoception and its functional consequence in the developing ovine lung - Project Summary The interoceptive link between the lung and CNS carries mechanical and irritant information to its first-order synapse in the brainstem. This information is critical in the newborn and adult for maintenance of pulmonary gas exchange in the face of behavioral changes and environmental stressors, and in orchestrating immune responses to viral, bacterial, and allergic pathogens. Although the fetal lung is richly innervated during development, the connectivity to the central nervous system (CNS), the extent to which these neurons help orchestrate lung and CNS formation over the course of development, and the role they play in function at birth remain largely unknown. This R01 application proposes to address this knowledge gap using a novel fetal sheep model. We hypothesize that intrinsic and extrinsic lung interoceptive units play a role in the normal development of the lung and central respiratory control centers. We will test this in the following aims: Aim 1: Traditional dye and novel viral track tracer techniques will be used in fetal sheep at various stages of lung development to delineate the location and connectivity of the interoceptive units within the lung, as well as first- and second-order central circuitry to and above the brainstem. The effect of surgical denervation on lung developmental morphology and the prevalence of various neural populations involved in chemo- and irritant sensation, including A- and C-fiber neurons involved in breathing control, and pulmonary neuroendocrine cells involved in pulmonary mechano- and chemosensation. Finally, single neuron RNAseq will be used to phenotypically characterize neurons within the fetal jugular and nodose ganglia at various stages of development. Aim 2: To test the necessity of interroception on fetal lung development and respiratory function after birth, fetuses in the canalicular stage will be subjected to either bilateral denervation of the lungs or periodic hyperstimulation of mechanoreceptors via overinflation for the remainder of gestation. Pulmonary vascular function, airway mechanics, and gas exchange will then be monitored following c-section delivery and in response to acute hypoxia and methacholine challenges, and responses will be compared to both sham and naive controls. Aim 3: Vagal ascending and descending nerve traffic will be recorded in fetuses instrumented with state-of-the-art cuff electrodes throughout fetal development and at birth. Custom time-series and spectral analysis software will be used to quantify changes in afferent/efferent vagal nerve signaling in response to pulmonary denervation, birth, and mechano- and chemosensory stimulations. The outcomes of these studies will fill in critical knowledge gaps of the role of interoception in lung development and function in a sheep model that has been a historically signature model of human perinatal lung development and physiology. Our proposed foundational work will inform future efforts focused on a variety of lung diseases in humans that originate during development, such as bronchopulmonary dysplasia, apnea of prematurity, sudden infant death syndrome, and asthma.


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 = $475,001 )
2025	2025	LOMA LINDA UNIVERSITY	11145 ANDERSON ST STE 203	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Research and Training in Complementary and Integrative Health	000	5	8/8/2025	NON-COMPETING CONTINUATION	$475,001
														Subtotal = $475,001

Issue Date FY: 2024 ( Subtotal = $488,875 )
2024	2024	LOMA LINDA UNIVERSITY	11145 ANDERSON ST	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Research and Training in Complementary and Integrative Health	000	4	9/3/2024	NON-COMPETING CONTINUATION	$488,875
														Subtotal = $488,875

Issue Date FY: 2023 ( Subtotal = $576,665 )
2023	2023	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Research and Training in Complementary and Integrative Health	000	3	8/16/2023	NON-COMPETING CONTINUATION	$576,665
														Subtotal = $576,665

Issue Date FY: 2022 ( Subtotal = $586,598 )
2022	2022	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Research and Training in Complementary and Integrative Health	000	2	9/8/2022	NON-COMPETING CONTINUATION	$586,598
														Subtotal = $586,598

Issue Date FY: 2021 ( Subtotal = $621,396 )
2021	2021	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Research and Training in Complementary and Integrative Health	000	1	9/1/2021	NEW	$616,549
2021	2021	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Research and Training in Complementary and Integrative Health	001	1	9/13/2021	NEW	$4,847
														Subtotal = $621,396

Grand Total All Awards = $2,748,535

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Unravelling lung interoception and its functional consequence in the developing ovine lung

Award Number: R01AT011691

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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