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Parsing cholesterol metabolite regulation of skin immunocytes in children to identify archetypes of human neonatal immune system

Award Number: U01AI168640
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/23/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Parsing cholesterol metabolite regulation of skin immunocytes in children to identify archetypes of human neonatal immune system - Project Summary The Type 3 cytokine (IL-17 and IL-22) producing lymphocytes (T3L) are strategically located at the mucocutaneous barrier tissues and serve as sentinels of tissue perturbations at the interface with the outside world. Skin resident T3L develop in early life and perform dual function: Early life, they promote tissue fitness by interacting with commensals to produce tonic IL-17; and throughout life, they defend against pathogens by rapid secretion of IL-17 essential for recruitment of neutrophils to inflamed tissues and fortifying the barrier tissues. Commensal dysbiosis by low dose antibiotics during early life of animals (E15 for mice and 24-28 weeks of gestation in humans) can lead to aberrant IL-17 production and is linked to metabolic dysfunctions observed in adults, including obesity. We discovered recently that a subset of T3L in mice can sense the dietary cholesterol metabolites oxysterols to calibrate their function. These cells arise immediately after birth in mice and they are the fastest (innate-like) lymphoid responders to tissue perturbations. The recognition of oxysterols by T3L is mediated by the G protein- coupled receptor GPR183, which is expressed by all T3L in mice and humans. Gpr183 has been genetically linked to psoriasis, colitis and Type 1 diabetes susceptibility in humans. In mice, early life skin T3L subset mediates IL-17-driven psoriatic responses downstream of Toll-like Receptor signaling in keratinocytes. This function is diet-modulated and dependent on GPR183, with high cholesterol diet leading to severe diseases, and conversely, vegetarian diet dampening IL-17 production and dramatically moderating disease severity. This discovery is the first to identify potential sensors of immune modulatory dietary metabolites on lymphocytes outside the gut. In humans T3L are known to be important in psoriasis in adults, but almost nothing is known about them in early life immune system. This gap in knowledge in large part exists because there is no systematic census of T3L and their interacting partners in mucocutaneous tissues of children. This proposal will fill this gap using innovative, unbiased, complementary single cell interrogation methods to catalogue all immune cell types and states in the skin of children from infancy to adulthood, stratified multi-parametrically, including BMI, dietary habits and infection history. The skin cell atlas of children will be instrumental in establishing correlation between dietary habits and propensity towards hyper inflammatory responses, modulated by skin-resident T3L. The genome-wide information rich map will identify gene networks that govern intercellular communications and cell lineage diversification, setting a major precedent of tissue immune systems relevant for childhood immunity, and accelerate progress towards defining mechanisms of early life immune system development.


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 = $792,392 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	2/12/2025	NON-COMPETING CONTINUATION	$792,392
														Subtotal = $792,392

Issue Date FY: 2024 ( Subtotal = $816,899 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	2/15/2024	NON-COMPETING CONTINUATION	$735,209
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$81,690
														Subtotal = $816,899

Issue Date FY: 2023 ( Subtotal = $816,899 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	3/1/2023	NON-COMPETING CONTINUATION	$816,899
														Subtotal = $816,899

Issue Date FY: 2022 ( Subtotal = $816,899 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	3/22/2022	NEW	$816,899
														Subtotal = $816,899

Grand Total All Awards = $3,243,089

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Parsing cholesterol metabolite regulation of skin immunocytes in children to identify archetypes of human neonatal immune system

Award Number: U01AI168640

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 03/23/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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