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Biophysical and functional characterization of immune-related regulatory elements and noncoding variants

Award Number: R01AI151051
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Susceptibility to diverse immune diseases has been associated with genetic differences that affect gene expression. Understanding the mechanisms by which these genetic differences lead to disease has been a central goal of genomic efforts aimed at describing disease mechanisms and identifying targets for therapeutic treatments. While large-scale studies have identified thousands of genetic differences associated with immune diseases, in most cases, it is not known which variants are causal and which are non-causal passenger variants. This is a considerable problem for the many variants that exists in non-coding regions of the genome for which function is difficult to predict. Thus, there is a critical need for the high-throughput experimental approaches to characterize the function and mechanism of the many non-coding variants associated with immune diseases. To tackle this challenge, we will use two complementary high-throughput approaches to study the impact of genetic variants on immune gene expression. We will use MPRAs (Massively Parallel Reporter Assays) to study the impact of genetic variants on gene expression. We will use our recently developed CASCADE (Comprehensive Assessment of Complex Assembly at DNA Elements) approach, in conjunction with mass spectrometry-based studies, to profile the impact of genetic variants on TF- cofactor complex binding. We will use these approaches to characterize (1) the impact of genetic variants on ~30 immune gene regulatory elements, and (2) ~5000 genetic variants found to be associated with immune disease or altered gene expression. Combining these approaches will address both function and biophysical mechanism of genetic variants in a cell- and stimulus-specific manner. Furthermore, as many regulatory cofactors can be inhibited with drugs, characterizing TF- cofactor complexes bound at genetic variants provides an opportunity to identify therapeutics to counteract their effects. Altogether, by integrating complementary, high-throughput approaches that directly account for effects of cell type and cell stimulation, the proposed studies will identify the mechanisms by which non-coding variants affect gene expression and immune diseases. Furthermore, these studies will lay a foundation for translating large-scale genetic studies into therapeutic approaches to treat for immune diseases.


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 = $499,637 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	2/6/2024	NON-COMPETING CONTINUATION	$499,637
														Subtotal = $499,637

Issue Date FY: 2023 ( Subtotal = $556,124 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	2/28/2023	NON-COMPETING CONTINUATION	$556,124
														Subtotal = $556,124

Issue Date FY: 2022 ( Subtotal = $558,635 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	2/15/2022	NON-COMPETING CONTINUATION	$558,635
														Subtotal = $558,635

Issue Date FY: 2021 ( Subtotal = $558,635 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	2	2/17/2021	NON-COMPETING CONTINUATION	$558,635
2021	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	10/21/2020	NEW	$0
														Subtotal = $558,635

Issue Date FY: 2020 ( Subtotal = $570,490 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	3/16/2020	NEW	$570,490
														Subtotal = $570,490

Grand Total All Awards = $2,743,521

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Biophysical and functional characterization of immune-related regulatory elements and noncoding variants

Award Number: R01AI151051

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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