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Using Multi-Omics to Define Regulators and Drivers of Granulomatous Inflammation and Chronic Beryllium Disease

Award Number: R01ES033678
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/09/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Using Multi-Omics to Define Regulators and Drivers of Granulomatous Inflammation and Chronic Beryllium Disease - PROJECT SUMMARY/ABSTRACT: The goal of this study is to define cell-specific regulatory networks and key drivers of cellular response to beryllium (Be) that result in the granulomatous lung disease, chronic beryllium disease (CBD), at the site of organ involvement. Relying on the complementary, unique expertise of investigative team we will define pathogenic pathways and risk factors for CBD, its precursor (Be sensitization; BeS) and similar environmentally induced diseases. Exposure to an inhaled Be antigen(s), in the setting of a genetically susceptible host, initiates a Th1 immune response, with antigen presentation occurring via HLA Class II on antigen presenting cell (APC) in the context of CD4+ T cells. Subsequently, CD4+ T cells and APCs are recruited to the lung, proliferate, produce cytokines and chemokines, and eventually form granulomas. An increased prevalence of HLA-DPB1 alleles with a glutamic acid at amino acid position 69 (E69) is found in CBD and BeS, although this variant is found in up to 40% of Be exposed workers without BeS or CBD, suggesting that other factors or forms of genetic regulation are important in disease pathogenesis. Growing data in other immune-mediated diseases suggests that epigenetic mechanisms in combination with genetic susceptibility and environment may help explain disease risk. Epigenetic modifications determine T cell and APC/macrophage differentiation and the ensuing immune response through DNA methylation and histone modifications of key genes and thus impact health and disease. Our previous work demonstrated DNA methylation changes associated with alterations in gene expression and disease state in bronchoalveolar lavage (BAL) cells of CBD subjects compared to BeS and controls, including pivotal immune response genes and networks. Single cell sequencing technologies have emerged as a key method to characterize novel cell population and cell-specific changes in gene expression. Based on this information, our hypothesis is that exposure to Be alters epigenetic marks, impacting gene expression and immune cell differentiation in cell-specific manner, and ultimately risk of granulomatous lung disease. We will test this hypothesis through three specific aims, focusing mainly on macrophages and CD4+ T cells but acknowledging that other cell populations are important and considering them in alternative approaches and future directions. In Aim 1 we will characterize the lung immune cell response to Be exposure using single cell ATAC-seq and CITE- seq to measure chromatin accessibility, gene expression levels and protein epitopes at four timepoints to define key drivers in specific cell populations. In Aim 2 we will validate the regulatory networks in uncultured lung samples, focusing on macrophages and CD4+ Tcells, using bulk ATAC- Me and RNA-sequencing. We will functionally validate the results from our multi-omic analysis from Aims 1 and 2 using CRSIPR-dCas9 to change methylation, chromatin accessibility, and gene expression at loci identified as key drivers of response to Be in cultured macrophage and T cell lines in Aim 3. Ultimately, this proposal will enhance our understanding of the novel genes, regulatory pathways and networks, and molecular mechanisms involved in CBD etiology.


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 = $556,630 )
2026	2026	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Environmental Health	000	5	12/30/2025	NON-COMPETING CONTINUATION	$556,630
														Subtotal = $556,630

Issue Date FY: 2025 ( Subtotal = $636,949 )
2025	2025	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Environmental Health	000	4	11/27/2024	NON-COMPETING CONTINUATION	$636,949
														Subtotal = $636,949

Issue Date FY: 2024 ( Subtotal = $646,640 )
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Environmental Health	000	3	11/29/2023	NON-COMPETING CONTINUATION	$646,640
														Subtotal = $646,640

Issue Date FY: 2023 ( Subtotal = $647,711 )
2023	2023	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Environmental Health	000	2	11/21/2022	NON-COMPETING CONTINUATION	$647,711
														Subtotal = $647,711

Issue Date FY: 2022 ( Subtotal = $659,638 )
2022	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Environmental Health	000	1	2/8/2022	NEW	$659,638
														Subtotal = $659,638

Grand Total All Awards = $3,147,568

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Using Multi-Omics to Define Regulators and Drivers of Granulomatous Inflammation and Chronic Beryllium Disease

Award Number: R01ES033678

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/09/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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