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Investigating fundamental signal transduction mechanisms impacted by FOXO transcription factors on NOTCH and JAK/STAT Pathways in stem cell contexts

Award Number: R16GM153687
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Investigating fundamental signal transduction mechanisms impacted by FOXO transcription factors on NOTCH and JAK/STAT Pathways in stem cell contexts - We propose a high impact collaborative project to overcome barriers to understanding the roles and regulation of Forkhead box subfamily O transcription factors FOXO -1, -3, and -4 (FOXO) in stem cell contexts. Stem cells repopulate the lining of the intestinal tract, muscle, and blood lineages, yet also drive devastating diseases such as cancer. Evolutionarily conserved, partially redundant FOXO transcription factors are needed for stem cell maintenance in a litany of contexts such as embryonic, cancer, mesenchymal, hematopoietic, and neural cell lineages, as well as direct specification of subsequent lineages in a context-dependent manner. Canonically, high PI3K output leads to cytoplasmic/inactive FOXO factors. Stem cells, however, are fundamentally rewired to have both high PI3K Pathway activity and nuclear/active FOXO factors. Prior work shows that FOXO factors directly bind to and activate stem genes in both embryonic stem cells and the poor prognosis cancer glioblastoma multiforme (GBM) to drive stem cell fate. However, the precise mechanisms utilized by FOXO transcription factors in driving stemness, hindering differentiation, and determining cell fate are incompletely understood. Our novel, preliminary insights indicate that nuclear-localized FOXOs engage both the NOTCH and JAK/STAT signaling pathways. Our preliminary evidence demonstrates a strong loss in the gene expression of NOTCH Pathway components NOTCH1 and NOTCH3, as well as their targets including HES1, in FOXO4 loss-of-function contexts. Our preliminary data indicates that FOXO factors share the ability to promote NOTCH output. Motivated by our preliminary findings and published work (by others), we propose examining whether FOXO - 1, -3, and -4 redundantly drive NOTCH1 and NOTCH3 gene expression in GBM and myoblasts. Our preliminary work with FOXO transcription factor disruption mutants shows that FOXO4 acts uniquely to hinder JAK/STAT3 activation and expression of targets IGF1, PDGF and TH. Of note, FOXO3 disruption led to a loss in STAT3 activation, underscoring unique contributions of FOXO factors to the JAK/STAT Pathway. We propose to dissect the ability of FOXO factors to differentially regulate the JAK/STAT Pathway in GBM and myoblast settings. Our long-term goal is to delineate FOXO-driven fundamental biological processes that aid stem cell maintenance and cell fate by promoting the NOTCH Pathway and differentially regulating the JAK/STAT Pathway. The proposed work will integrally involve student researchers and will promote the research environment at UTRGV.


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 = $148,000 )
2025	2025	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	2	8/18/2025	NON-COMPETING CONTINUATION	$148,000
														Subtotal = $148,000

Issue Date FY: 2024 ( Subtotal = $148,000 )
2024	2024	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	1	9/19/2024	NEW	$148,000
														Subtotal = $148,000

Grand Total All Awards = $296,000

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Investigating fundamental signal transduction mechanisms impacted by FOXO transcription factors on NOTCH and JAK/STAT Pathways in stem cell contexts

Award Number: R16GM153687

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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