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Post-GWAS Functional Genomics Analysis to Define Pathogenic Mechanisms for Pulmonary ArterialHypertension

Award Number: K08HL161435
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Post-GWAS Functional Genomics Analysis to Define Pathogenic Mechanisms for Pulmonary ArterialHypertension - PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is an enigmatic and morbid disease where insights are emerging regarding genetic susceptibility to disease. Genome-wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are associated with PAH risk and severity. Yet, the GWAS-reported SNPs are only tags of haplotype SNPs in linkage disequilibrium (LD). Thus, the tag SNP may simply be linked to the true disease-causing functional SNP (fSNP). GWAS also only reveal statistical associations, and it has been challenging to define the mechanisms underlying the contribution of the PAH-associated fSNPs, which are mostly located in the non-coding regions, to the pathogenesis of PAH. Using our recently developed post-GWAS functional genomics platform, I identified a non-coding fSNP rs4738801 in the genomic locus of SOX17 gene, a known endothelial effector increasingly being studied in PAH pathogenesis. I identified that the transcription factor FUBP1 binds to the rs4738801 risk allele C in an allele-imbalanced manner, with lower affinity to risk allele C than non-risk allele G, providing an underlying mechanism how this fSNP regulates the PAH pathogenic gene SOX17 and contributes to the PAH risk. FUBP1 controls PAH-associated pathophenotypes in pulmonary arterial endothelial cells (PAECs). Downregulated by the major acquired PAH trigger hypoxia, FUBP1 and its target gene SOX17 are decreased in lungs and isolated pulmonary ECs from PAH patients and mouse models. A 3.77- fold enrichment of fSNP rs4738801 risk allele C was found in patients with PAH induced by hypoxia, supporting a pathogenic mechanism of a hypoxia-sensitive pathway (FUBP1-SOX17) combined with a disease susceptible genotype (risk allele C) for clinical manifestation of this disease. Based on these data, I hypothesize that the allele-imbalanced binding of transcription factor FUBP1 to fSNP rs4738801 defines the genomic architecture contributing to the SOX17-dependent genetic susceptibility of PAH. I further postulate that the downregulation of FUBP1-SOX17 by hypoxia contributes to the acquired pathogenesis of PAH. To test this hypothesis, I propose 2 specific aims: 1) To define the allele-specific role of fSNP rs4738801 in promoting endothelial dysfunction in PAH in gene-edited iPSC-ECs and PAH patient lung tissues; and 2) To determine the role of FUBP1 in controlling SOX17 and PAH in mouse models. Accomplishing these aims will facilitate my enduing career goal of becoming an independent physician-scientist in PAH functional genomics research. Immediate scientific development objectives include: 1) To develop expertise in PAH genetics and functional genomics; 2) To develop expertise in iPSC-EC biology and CRISPR-Cas9 gene-editing techniques; and 3) To develop skills of in vivo gene expression manipulation and become proficient in the assessment of PAH in animal models. The proposed training plan will provide me with the opportunity to expand my knowledge base to include advanced research techniques in PAH pathogenesis. The resources and expertise of my mentors, contributors, and the rich research environment at the University of Pittsburgh will assure my successful transition to an independent investigator.


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	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	001	3	3/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$103,867
2025	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	2	3/18/2025	NON-COMPETING CONTINUATION	-$103,867
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $160,801 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	001	3	9/2/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$160,801
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	2	8/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $160,801

Issue Date FY: 2023 ( Subtotal = $160,721 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	2	8/26/2023	NON-COMPETING CONTINUATION	$160,721
														Subtotal = $160,721

Issue Date FY: 2022 ( Subtotal = $160,721 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	1	9/5/2022	NEW	$160,721
														Subtotal = $160,721

Grand Total All Awards = $482,243

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Post-GWAS Functional Genomics Analysis to Define Pathogenic Mechanisms for Pulmonary ArterialHypertension

Award Number: K08HL161435

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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