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Promoter interactome-aided mapping of unexplored CVID genetic landscapes

Award Number: R01AI146026
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/16/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Promoter interactome-aided mapping of unexplored CVID genetic landscapes - PROJECT SUMMARY/ABSTRACT Common variable immunodeficiency (CVID) is a primary disease of germinal center (GC) dysfunction, yet most CVID mechanistic investigations have utilized patient blood samples, which do not contain bona fide GC cells. Similarly, genome-wide association studies (GWAS) of CVID patients have identified many disease-associated single nucleotide polymorphisms (SNPs), yet most lie in non-coding DNA and are of unclear relevance to disease pathogenesis. The long-range goal of the proposed work is to determine the full genetic basis of CVID. The objective of this grant is to determine which non-coding regions of DNA contribute to GC dysfunction. The working hypothesis is that CVID GWAS SNPs point to important non-coding genomic regions that interact with promoters of genes key to GC lymphocyte function. Further, genetic variation altering gene promoter interactions, or damage to these genes themselves, will lead to GC dysfunction and eventually the symptoms of CVID. Our rationale is that identifying gene promoter interactions critical to GC homeostasis will provide new diagnostic and therapeutic opportunities for patients suffering from diseases of GC dysfunction including, but not limited to, CVID. Our specific aims will test the following hypotheses: (Aim 1) CVID GWAS associated regions euchromatically interact with gene promoters in T follicular helper cells (Tfh) and/or follicular B cells (FO B cells); (Aim 2) these interactions influence gene expression; (Aim 3) non-coding variants altering gene expression or variants damaging coding genes are enriched in CVID patients and that rhese variants alter Tfh and FO B cell function. The contribution is significant because cataloguing the genes and gene promoter contacts vital to GC homeostasis/dysfunction will offer new disease discovery opportunities and provide new molecules to target with personalized therapies. The proposed work is innovative because we are reinterpreting published GWAS with a suite of interlocking genome-scale technologies capable of annotating individual SNPs with overlapping layers of cell type-specific epigenetic information including promoter contacts, chromatin availability and gene expression. Further, we are verifying our findings in CVID exomes and genomes, with genetically modified cell-lines, with patient lymph nodes and in co-cultures that recapitulate key transcriptional features of the GC environment.


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 = -$9 )
2026	2023	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	12/17/2025	NON-COMPETING CONTINUATION	-$9
														Subtotal = -$9

Issue Date FY: 2023 ( Subtotal = $570,236 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	6/12/2023	NON-COMPETING CONTINUATION	$570,236
														Subtotal = $570,236

Issue Date FY: 2022 ( Subtotal = $570,236 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	6/7/2022	NON-COMPETING CONTINUATION	$570,236
														Subtotal = $570,236

Issue Date FY: 2021 ( Subtotal = $570,236 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	7/2/2021	NON-COMPETING CONTINUATION	$570,236
														Subtotal = $570,236

Issue Date FY: 2020 ( Subtotal = $568,348 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	7/1/2020	NON-COMPETING CONTINUATION	$568,348
														Subtotal = $568,348

Issue Date FY: 2019 ( Subtotal = $606,348 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	7/16/2019	NEW	$606,348
														Subtotal = $606,348

Grand Total All Awards = $2,885,395

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Promoter interactome-aided mapping of unexplored CVID genetic landscapes

Award Number: R01AI146026

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/16/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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