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Biology of Lymphangiogenesis in the Adult Lung

Award Number: R01HL164612
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Biology of Lymphangiogenesis in the Adult Lung - PROJECT SUMMARY/ABSTRACT The lung’s lymphatic system plays a critical role in lung health by maintaining fluid homeostasis and by serving as a conduit for immune cell trafficking. Despite the importance of this network however, there are significant knowledge gaps in the basic biology of this system and its key cellular constituent, the lymphatic endothelial cell (LEC). For one, very little is known regarding the origin and replacement of lung LECs in adult life and how different origins and micro-anatomical locations of LECs might be associated with different roles, specifically in immune responses. Indeed, whether lung LECs comprise a heterogeneously and functionally distinct set of cell subtypes or a largely homogenous population is unknown. After instillation of flu into the mouse left lung lobe, we observed a local and vigorous lymphangiogenic reaction manifested by early vessel dilation followed by expansion of the lymphatic network itself. This is associated with a significant 1.5-2-fold increase of LECs at 7 days post-infection (dpi) and a significant 2-3-fold increase at 21 dpi, a time when the virus is cleared. Edu labeling demonstrated that 20% of LECs are proliferating at 7 dpi vs. <1% in control mice. These data along with observations suggesting 2 distinct sources of adult LECS, one fetal and from a venous origin, and one post- natal and from a myeloid origin, underscore the potential for LEC heterogeneity both functionally and micro- anatomically. This will be addressed in Aim 1 by evaluating the role and localization of these 2 sources of LECs during adult lung homeostasis and viral-induced lymphangiogenesis by lineage tracing. These studies will be supplemented by single nuclear RNA sequencing in Aim 2 to generate LEC specific genetic information that will be key to understanding LEC heterogeneity and immune response to infection, along with derivation of LEC subset tissue localization markers. We also found that the flu-infected lung is characterized by decreased LEC nuclear localization of YAP and TAZ, which are the primary transcriptional effectors in the Hippo signaling pathway. This highly conserved pathway is a central regulator of cell phenotype in many biological systems with decreased nuclear YAP/TAZ signifying signal inhibition. Taken together, these findings suggest that the status of Hippo signaling may be a key factor regulating LEC proliferation and phenotype. Lastly, we observed vigorous LEC proliferation in the contralateral uninfected lung, suggesting the interesting possibility that LEC proliferation is a systemic response to flu. These issues will be further studied in Aim 3 by the selective deletion of hippo signaling in LECs and by examining lymphangiogenesis in liver and heart in our flu model. In sum, we posit that the state-of-the art shows a pronounced need for basic information that can resolve fundamental questions in the field of lung lymphatic biology. With strong background data and robust models, we believe that the studies in this grant will help to resolve these basic questions, and as result will expand and deepen our understanding of LEC origin, mechanism of expansion, heterogeneity, function, and phenotype regulation.


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	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	4	12/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $558,360 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	4	7/15/2025	NON-COMPETING CONTINUATION	$558,360
														Subtotal = $558,360

Issue Date FY: 2024 ( Subtotal = $558,108 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	3	7/18/2024	NON-COMPETING CONTINUATION	$558,108
														Subtotal = $558,108

Issue Date FY: 2023 ( Subtotal = $595,898 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	2	6/27/2023	NON-COMPETING CONTINUATION	$595,898
														Subtotal = $595,898

Issue Date FY: 2022 ( Subtotal = $569,498 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	1	6/6/2022	NEW	$569,498
														Subtotal = $569,498

Grand Total All Awards = $2,281,864

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Biology of Lymphangiogenesis in the Adult Lung

Award Number: R01HL164612

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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