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Defining the role of the nuclear lamina in the mechanical regulation of lung fibrosis

Award Number: F31HL158119
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/16/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Defining the role of the nuclear lamina in the mechanical regulation of lung fibrosis - PROJECT SUMMARY / ABSTRACT Fibrosis is the excessive excretion of extracellular matrix (ECM) proteins, which leads to tissue stiffening and decreased organ function. Fibroblasts and myofibroblasts are the primary cell types responsible for ECM deposition. Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic disease of unknown origin. The role of biochemical signaling through the TGFb signaling pathway is a well-established driver of IPF and other fibrotic disease. There is also an emerging and evolving role for mechanical signaling in the regulation of ECM deposition in fibroblasts and the progression of fibrosis. The molecular mechanism by which mechanical inputs are integrated with biochemical signals to regulate fibrosis remains enigmatic. Work from our lab has implicated the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex as a new regulator of fibrosis; ablation of the LINC complex component SUN2 in a Sun2-/- mouse model is protective in the context of hypertrophy-coupled cardiac fibrosis and injury-induced lung fibrosis. Given the established role of LINC complexes in transmitting mechanical force from the cell surface to the nucleus, a compelling hypothesis is that LINC complexes contribute to mechanotransduction during fibrosis progression. The overall objective of this proposal is to define the molecular mechanisms by which loss of SUN2 leads to protection from fibrosis. The proposed research will investigate this objective in two specific aims. Aim 1 will define the integration of biochemical (modulating TGFb and TGFb receptor) and mechanical (modulating cell substrate stiffness) inputs in the regulation of pro-fibrotic gene expression and attainment of pro-fibrotic phenotypes in primary human and mouse lung fibroblasts. The contexts and mechanism by which SUN proteins influence integration of pro-fibrotic signals to regulate gene expression will be interrogated using CRISPR-based gene editing, transcriptome analysis, and imaging techniques. Aim 2 will define the impact of loss of SUN proteins on both chromatin state and the established transducers of TGFb signaling, the Smad family of transcription factors, using a combination of genomic techniques and imaging approaches. This proposal will address fundamental aspects of gene regulation as it pertains specifically to the progression of lung fibrosis, in line with the mission of the National Heart, Lung, and Blood Institute. The trainee will be immersed in a supportive, collaborative and interdisciplinary environment while completing the proposed project under the rich support and mentorship of the sponsor/co-sponsor, ultimately positioning her to approach fundamental questions through a translational lens. She will improve her experimental design skills, obtain training in rigorous analysis of experimental data, and expand her technical skillset to include methods from genomics to imaging of tissue. The trainee will also have ample access to opportunities for improving oral presentation, writing, mentorship, scientific outreach skills.


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 = -$46,556 )
2024	2023	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	2	2/26/2024	NON-COMPETING CONTINUATION	-$8,930
2024	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	2	10/16/2023	NON-COMPETING CONTINUATION	-$37,626
														Subtotal = -$46,556

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	2	3/31/2023	NON-COMPETING CONTINUATION	$942
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	2	1/18/2023	NON-COMPETING CONTINUATION	$46,752
														Subtotal = $47,694

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	1	12/15/2021	NEW	$46,036
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	002	1	6/24/2022	NEW	$0
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	1	6/24/2022	NEW	$716
														Subtotal = $46,752

Grand Total All Awards = $47,890

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Defining the role of the nuclear lamina in the mechanical regulation of lung fibrosis

Award Number: F31HL158119

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/16/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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