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The CFTR Interactome

Award Number: R01HL165168
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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The CFTR Interactome - Project Summary Cystic Fibrosis (CF) is caused by mutation of the CFTR gene and is one of the most common inherited childhood diseases, impacting 1 in 4,000 children born in the US (www.cff.org). Today, CF disease symptoms in patients with the most common mutation (∆F508 CFTR) can be improved with three different drug combinations. However, the drugs have negative side effects that reduce patient compliance to therapeutic regimens and pose long-term health risks. Additionally, many other common CF-causing mutations respond poorly or not at all to any of the current CF drugs, leaving CF patients carrying these mutations only with symptomatic therapy. Efforts to develop new compounds for such CF variants are hampered by the lack of protein structures that would reveal the conformational defects of these variants, mostly due to technical difficulties in expressing and purifying sufficient quantities of these unstable proteins. To characterize the conformational defects of misfolded CFTR variants and to aid in the development of new therapies, we previously developed Covalent Protein Painting (CPP), a novel method for in vivo structural characterization of proteins by mass spectrometry. Here, we propose to develop a more sensitive and multiplexable CPP method, named bioTMT-CPP, that will facilitate detection and comparison of CFTR conformational changes between samples. The new method will facilitate the characterization of conformational defects in misfolded CFTR variants that are refractory to current therapies. Furthermore, our approach has the potential to pinpoint drug binding sites and identify the mechanism of action of current CF drugs, which remain unknown for three of the four active compounds. Such knowledge will help to rationalize drug combination therapies. We also propose to functionally characterize a novel CFTR conformation that we discovered by CPP and that is attained by misfolded and inactive CFTR, likely during protein trafficking. Insight into the molecular mechanisms that stabilize this conformation as well as those that release it into an active conformation will be invaluable for further corrector drug development and will benefit all CF patients.


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 = $539,304 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Lung Diseases Research	000	4	7/11/2025	NON-COMPETING CONTINUATION	$539,304
														Subtotal = $539,304

Issue Date FY: 2024 ( Subtotal = $528,518 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Lung Diseases Research	001	3	7/12/2024	NON-COMPETING CONTINUATION	-$10,786
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Lung Diseases Research	000	3	7/11/2024	NON-COMPETING CONTINUATION	$539,304
														Subtotal = $528,518

Issue Date FY: 2023 ( Subtotal = $540,104 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Lung Diseases Research	000	2	7/17/2023	NON-COMPETING CONTINUATION	$540,104
														Subtotal = $540,104

Issue Date FY: 2022 ( Subtotal = $539,068 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Lung Diseases Research	000	1	8/5/2022	NEW	$539,068
														Subtotal = $539,068

Grand Total All Awards = $2,146,994

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The CFTR Interactome

Award Number: R01HL165168

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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