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Mechanisms controlling distinct growth and functional characteristics of the perinatal and adult thymus

Award Number: P01AI139449
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary The integrated hypothesis of this Program proposal is that age-associated cellular and molecular features of the mouse thymus microenvironment, mirrored by similar features in the human thymus, play a major role in shaping the distinct functional potential of T cells that emigrate from the thymus during the perinatal versus juvenile periods. Currently, there is little information in mice, and even less in humans, on changes in the composition and function of thymic epithelial cells (TECs), hematopoietic antigen presenting cells (HAPCs), and other stromal cell subsets during this transition. Given that T cells with effector and regulatory functions are vital for newborn health, the Program research objectives are to: 1) identify changes in the composition and organization of TECs, HAPCs and other thymus stromal cells over the perinatal to juvenile transition in both mice and humans; 2) map transcriptional changes in these cellular subsets that regulate their proliferation, differentiation, function and cross-talk; and 3) determine how such changes impact the ability of the perinatal thymic environment to generate T cells with distinct functional capabilities. The Program is structured to use scRNA-seq and multiplex imaging to collaboratively identify candidate cell populations and molecular mechanisms underlying functionally significant changes in mouse and human thymus microenvironments across the perinatal to juvenile transition. In the discovery phase, RPs will generate scRNA- seq datasets of TECs (RP1), stromal cells (RP2) and HAPCs (RP3) from mouse and human (Core C) thymus. These datasets will be analyzed by Core B to identify cellular and molecular candidates. In the prioritization phase, RPs will determine which candidates are conserved across species with Core B. RPs will then collaborate to use multiplex imaging to visualize changes in location and/or interactions of these candidates during the transition that may mediate important biological functions. Both species conservation and imaging results will provide a rationale to prioritize cell subsets and molecular pathways for functional testing. In the testing phase, each RP will assess novel, as well as previously identified candidates, for functional significance according to Project specific goals. Collectively, these parallel scRNA-seq and imaging experiments in the three RPs will synergize to: 1) identify changes in the transcriptional profiles, cellular composition and organization of the thymus microenvironment over the perinatal to juvenile transition in both mice and humans; and 2) enable us to test which changes regulate proliferation, differentiation, and function of these subsets across the transition with downstream consequences for perinatal immune function. Program components are: RP1 (Richie): Molecular mechanisms controlling TEC dynamics and lineage hierarchies in the perinatal thymus RP2 (Manley): The role of Foxn1 in controlling the transition from thymus expansion to homeostasis RP3 (Ehrlich): Differential contribution of thymic APCs to central tolerance during the perinatal to adult transition Core A (Richie): Admin. Core; Core B (Yi): Bioinformatics/Biostats Core; Core C: (Hale) Human Thymus Core


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 = $2,288,223 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	5	8/16/2024	NON-COMPETING CONTINUATION	$2,288,223
														Subtotal = $2,288,223

Issue Date FY: 2023 ( Subtotal = $2,800,314 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	4	8/23/2023	NON-COMPETING CONTINUATION	$505,000
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	4	8/15/2023	NON-COMPETING CONTINUATION	$2,295,314
														Subtotal = $2,800,314

Issue Date FY: 2022 ( Subtotal = $2,309,862 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	3	8/23/2022	NON-COMPETING CONTINUATION	$2,309,862
														Subtotal = $2,309,862

Issue Date FY: 2021 ( Subtotal = $2,306,217 )
2021	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	2	8/17/2021	NON-COMPETING CONTINUATION	$2,306,217
														Subtotal = $2,306,217

Issue Date FY: 2020 ( Subtotal = $2,326,438 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	9/1/2020	NEW	$2,326,438
														Subtotal = $2,326,438

Grand Total All Awards = $12,031,054

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Mechanisms controlling distinct growth and functional characteristics of the perinatal and adult thymus

Award Number: P01AI139449

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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