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Role of interleukin-6 signaling on T cell potential of aged hematopoietic stem cells and thymic progenitors

Award Number: F30AG086001
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Role of interleukin-6 signaling on T cell potential of aged hematopoietic stem cells and thymic progenitors - PROJECT SUMMARY/ABSTRACT T cell production declines with age and contributes to decreased immune function and increased susceptibility to infections and cancers in older adults. This decline in T cell output may be due to changes in the aged progenitor cells and/or changes in the thymic microenvironment. T cells develop from hematopoietic stem cells (HSCs) and progenitors that enter the thymus, an organ known to atrophy with age. Previous studies looking at T cell potential from aged HSCs have been limited by the assays available; determining T cell output in vivo has relied on hematopoietic transplantation models and is confounded by the long process of engraftment and thymic recruitment. While some in vitro models have looked at T cell output from aged HSCs and progenitors, these methods often start with a heterogenous population of cells and produce mixed conclusions about T cell potential. This proposal seeks to overcome these challenges by studying single, phenotypically-defined aged and young HSCs and progenitors to determine T cell output and development. Further, we will determine whether a pro-inflammatory signaling pathway enhanced in aging plays a role in driving reduced thymopoiesis with age. In this proposal, Specific Aim 1 will determine the role of HSC and progenitor age on T cell development using our in vitro Artificial Thymic Organoid (ATO) system. The ATO fully recapitulates all stages of T cell development from a single HSC or progenitor. Preliminary data from our lab suggests that aged stem cells exhibit differences at early stages of T cell development and removing aged stem cells from their inflamed microenvironment ultimately restores their ability to produce comparable T cell numbers, emphasizing the importance of inflammatory factors in the microenvironment. Specific Aim 2 will evaluate a specific signaling pathway enhanced in aging and its effects on T cell production using a novel mouse model. Levels of the inflammatory cytokine interleukin-6 (IL-6) increase in the aged bone marrow and thymus, and IL-6 may drive changes in the aged HSC pool (resulting in more myeloid- biased HSCs) and thymic atrophy. IL-6 requires signaling through glycoprotein 130 (gp130), and our collaborators identified a signaling modality within the gp130 receptor that produced regenerative effects in mouse models of wound healing and osteoarthritis when inactivated. In our preliminary data, we show that these mutant mice also have greater thymocyte numbers, prompting us to investigate whether signaling through this specific part of the IL-6 gp130 receptor mediates reduced thymopoiesis with age. Our results will improve our understanding of the aging immune system and inform potential therapies for regenerative medicine. Successful completion of these aims is a critical component of a comprehensive training plan, in which I will gain skills in experimental design, data analysis, scientific communication, and mentorship to grow as a future physician scientist. I will be supported by my sponsor, Dr. Gay Crooks, in a collaborative training environment at UCLA.


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 = $41,771 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	2	6/25/2025	NON-COMPETING CONTINUATION	$41,771
														Subtotal = $41,771

Issue Date FY: 2024 ( Subtotal = $40,967 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	002	1	6/25/2024	NEW	$0
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	001	1	4/30/2024	NEW	$1,280
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	1	12/14/2023	NEW	$39,687
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	003	1	6/25/2024	NEW	$0
														Subtotal = $40,967

Grand Total All Awards = $82,738

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Role of interleukin-6 signaling on T cell potential of aged hematopoietic stem cells and thymic progenitors

Award Number: F30AG086001

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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