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Understanding Mechanisms Underlying Chronic Stress-Induced Asthma in Children by Population and Single-Cell Epigenomics Approaches

Award Number: R01MD015409
ORGANIZATION: NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY Asthma is a severe long-term disease of the lungs affecting millions of children in the US. An infection by Rhinovirus (RV) is the most common trigger of an asthma attack which can be life threating for children with a pre-existing condition. There are significant racial and ethnic disparities in asthma-related conditions where African American and Hispanic children are more likely to have a diagnosis of asthma and significantly higher asthma-related morbidity in comparisons with non-Hispanic white children. Genetic factors alone or in combination with differences in environment exposures or lifestyle are important but have not been able to fully explain observed disparities. Social environment such as chronic stressors experienced by racial and ethnic minority groups have been linked to increased susceptibility to infection and chronic illness including asthma. We hypothesize that social disadvantages during childhood result in long-lasting epigenetic alterations in key regulatory regions impacting immune cell gene function that negatively impacts antiviral defense and subsequently increase the risk of asthma. Our goal is to combine population-based epigenome mapping in nasal mucosa with single immune cell analysis in large pediatric asthma cohorts of African American children with detailed information about asthma and viral status as well as chronic stress exposures of several domains. In Aim 1, we will implement an epigenome enrichment assay using our Methylation Capture Sequencing approach to query the complete functional methylome in nasal mucosa (estimated to cover ~3M dynamic CpGs) derived from thousands of children. We will deploy the approach in well-characterized pediatric cohorts to explore predictive power of nasal epigenome signatures to capture chronic stress, viral infection along with asthma phenotypes. In Aim 2, we will profile the immune cell landscape by high-throughput transcriptomic and epigenome assays at single-cell resolution in hundreds of children with asthma. We will focus our single-cell profiling efforts in blood derived from RV infected children that are exposed to high vs. low levels of chronic stress to characterize immune cell signaling and viral response mechanisms epigenetically altered as a consequence of social experiences. In Aim 3, we will perform in vitro validations of RV response in primary macrophages differentiated from circulating monocytes from children that are discordant for chronic stress exposure. We will perform detailed single-cell transcriptome and epigenome mapping before and after in vitro infection with RV which will allow us to quantify the effects of social disadvantages on immune gene expression at baseline and in response to RV infection. Overall, our program will provide new insight into how genes and the social environment combine to influence heterogeneity in the response to environmental stressors and contribute to the health disparity seen in children with asthma.


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 = $617,464 )
2024	2024	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	000	5	5/3/2024	NON-COMPETING CONTINUATION	$617,464
														Subtotal = $617,464

Issue Date FY: 2023 ( Subtotal = $636,561 )
2023	2023	CHILDRENS MERCY HOSPITAL	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	001	4	4/30/2023	NON-COMPETING CONTINUATION	$636,561
2023	2022	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	000	3	10/20/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $636,561

Issue Date FY: 2022 ( Subtotal = $1,093,259 )
2022	2022	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	001	3	8/19/2022	SUPPLEMENT FOR EXPANSION	$301,930
2022	2022	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	000	3	4/16/2022	NON-COMPETING CONTINUATION	$636,561
2022	2022	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	002	3	8/21/2022	SUPPLEMENT FOR EXPANSION	$154,768
														Subtotal = $1,093,259

Issue Date FY: 2021 ( Subtotal = $643,818 )
2021	2021	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	000	2	4/14/2021	NON-COMPETING CONTINUATION	$643,818
														Subtotal = $643,818

Issue Date FY: 2020 ( Subtotal = $658,172 )
2020	2020	CHILDREN'S MERCY HOSPITAL, THE	2401 GILLHAM RD	KANSAS CITY	MO	64108	JACKSON	USA	Minority Health and Health Disparities Research	000	1	8/26/2020	NEW	$658,172
														Subtotal = $658,172

Grand Total All Awards = $3,649,274

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Understanding Mechanisms Underlying Chronic Stress-Induced Asthma in Children by Population and Single-Cell Epigenomics Approaches

Award Number: R01MD015409

ORGANIZATION: NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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