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Transfer RNAs in Hematopoietic Stem Cell Function

Award Number: R01HL165172
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Transfer RNAs in Hematopoietic Stem Cell Function - ABSTRACT Hematopoietic Stem Cells (HSCs) produce all cells of the blood lineage throughout life. Defects in HSC self- renewal can lead to immunological defects, anemia, and bone marrow failure. Enhanced HSC self-renewal can result in hematopoietic malignancies. Thus, precise regulation of HSC self-renewal is essential for maintaining hematopoietic and human health. Our previous work has shown that adult HSCs tightly control protein synthesis and that modest changes in protein synthesis impair HSC self-renewal and function. However, the mechanisms that regulate mRNA translation in HSCs remain largely unknown. Transfer RNAs (tRNAs) are non-coding adaptor RNAs critical for mRNA translation that are encoded by hundreds of genes in the mammalian genome, with multiple functional genes capable of decoding virtually every codon. We previously showed that the tRNA repertoire influences neuronal function but the effect of changes in tRNA expression on hematopoietic cells is unknown. In preliminary studies, we found that loss of n-Tr22, a member of the five gene arginine UCU tRNA family significantly impairs HSC maintenance and self-renewal, and this is exacerbated in a sensitized genetic background lacking the ribosome rescue factor Gtpbp2, resulting in a complete loss of adult, but not fetal HSCs. We hypothesize that the sensitivity of adult HSCs to the n-Tr22 mutation may be due to differences in the tRNA repertoire between adult HSCs and restricted progenitors, and between HSCs at different developmental stages. The impact of tRNA mutations may be further influenced by differential codon usage in the transcriptome of these cell populations. Finally, there may be cell-type-specific differences in the signaling pathways activated by loss of a tRNA. We propose to test this hypothesis by using chromatin immunoprecipitation and sequencing to determine the tRNA repertoire in the hematopoietic system. We will also analyze how this tRNA mutation influences the maintenance and function of HSCs in the presence and absence of the Gtpbp2 mutation using flow cytometry and long-term multilineage reconstitution assays. Finally, we will determine the effects of the loss of n-Tr22 and Gtpbp2 on protein synthesis and gene expression by incorporation of a puromycin analog, ribosome profiling, and RNA-sequencing. The results from this grant will not only shed light on the role of tRNAs in regulating mRNA translation in the hematopoietic system, but also provide a means to understand the role of these genes in the phenotypic heterogeneity common to many human hematopoietic disorders.


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 = $316,000 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Blood Diseases and Resources Research	000	3	7/21/2025	NON-COMPETING CONTINUATION	$316,000
														Subtotal = $316,000

Issue Date FY: 2024 ( Subtotal = $316,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Blood Diseases and Resources Research	000	2	7/26/2024	NON-COMPETING CONTINUATION	$316,000
														Subtotal = $316,000

Issue Date FY: 2023 ( Subtotal = $316,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Blood Diseases and Resources Research	000	1	8/1/2023	NEW	$316,000
														Subtotal = $316,000

Grand Total All Awards = $948,000

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Transfer RNAs in Hematopoietic Stem Cell Function

Award Number: R01HL165172

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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