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Discovery of novel mechanisms that impact CFTR translation and contribute to cystic fibrosis pathogenesis

Award Number: R01HL136414
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Discovery of novel mechanisms that impact CFTR translation and contribute to cystic fibrosis pathogenesis Abstract This project is intended to advance high throughput yeast phenomics technology and provide new mechanistic information regarding a model genetic disease, cystic fibrosis (CF). When clinically significant mutations in the CF transmembrane conductance regulator (CFTR) are engineered in a yeast homolog (YOR1), genome-wide phenomic analysis using the yeast deletion strain library (YDSL) identifies novel pathways that impact CF molecular phenotype. New experimental targets for CF therapy also result from studies of this type. Under Specific Aim 1 of the renewal, we show ways in which genome-wide yeast studies can advance understanding of CFTR variants including nonsense (Type 1) and severe folding (Type 2) defects for which no “personalized” modulator treatment currently exists. We also demonstrate phenomics can be applied to elucidate pathways necessary for pharmacologic rescue. Specific Aim 2 engages leading-edge technology (ribosomal profiling, deep-sequencing based on modification mapping (Psi-Seq)) to delve deeply into novel (and unexpected) mediators of CFTR biogenesis based on analysis of mammalian translational efficiency. In particular, we examine the role of ribosomal “collisions” or “queueing” described by phenomic analysis, and mRNA pseudouridinylation for effects on CFTR translation and protein synthesis. Specific Aim 3, applies innovative CF cell models to establish clinical significance of findings from Aims 1 and 2. The proposed studies will test important hypotheses relevant to CF pathogenesis, provide new knowledge regarding translational velocity and mRNA utilization during CFTR expression, and show that ribosomal collisions and pseudouridinylation contribute to cystic fibrosis. Our findings will also help advance new targets for treating refractory forms of CF. Lessons learned from the studies can be applied to many other inherited and serious human illnesses.


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 = $0 )
2025	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	7	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $540,504 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	002	7	6/12/2024	NON-COMPETING CONTINUATION	$44,123
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	001	7	4/3/2024	NON-COMPETING CONTINUATION	$0
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	7	12/22/2023	NON-COMPETING CONTINUATION	$496,381
														Subtotal = $540,504

Issue Date FY: 2023 ( Subtotal = $551,534 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	6	12/26/2022	NON-COMPETING CONTINUATION	$496,381
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	001	6	3/10/2023	NON-COMPETING CONTINUATION	$55,153
														Subtotal = $551,534

Issue Date FY: 2022 ( Subtotal = $579,784 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	003	5	5/25/2022	COMPETING CONTINUATION	$182,023
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	5	12/31/2021	COMPETING CONTINUATION	$579,784
2022	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	002	4	5/25/2022	NON-COMPETING CONTINUATION	-$182,023
2022	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	001	4	1/4/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $579,784

Issue Date FY: 2021 ( Subtotal = $556,180 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$55,619
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	4	11/30/2020	NON-COMPETING CONTINUATION	$500,561
														Subtotal = $556,180

Issue Date FY: 2020 ( Subtotal = $556,180 )
2020	2020	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	3	11/27/2019	NON-COMPETING CONTINUATION	$528,371
2020	2020	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	001	3	1/25/2020	NON-COMPETING CONTINUATION	$27,809
														Subtotal = $556,180

Issue Date FY: 2019 ( Subtotal = $556,180 )
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	2	12/12/2018	NON-COMPETING CONTINUATION	$556,180
														Subtotal = $556,180

Issue Date FY: 2018 ( Subtotal = $584,180 )
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Lung Diseases Research	000	1	12/12/2017	NEW	$584,180
														Subtotal = $584,180

Grand Total All Awards = $3,924,542

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Discovery of novel mechanisms that impact CFTR translation and contribute to cystic fibrosis pathogenesis

Award Number: R01HL136414

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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