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Tools for reversible short-term degradation of TCF-1 to address its molecular functions

Award Number: R21AI176254
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Tools for reversible short-term degradation of TCF-1 to address its molecular functions - Tools for reversible short-term degradation of TCF-1 to address its molecular functions Abstract During T cell development, the T cell-specific DNA binding protein TCF-1 performs multiple stage and lineagespecific epigenetic functions. TCF-1 has been associated with both enhancing and reducing chromatin accessibility and gene expression depending on the region it binds to and the proximal binding of other regulators. There is a gap in our knowledge in how TCF-1 leverages its stage and context-specific functions. TCF-1 is essential for initiating the commitment of progenitor cells to the T-cell lineage and it modulates the epigenetic and transcription profiles of developing T-cells at almost every developmental transition and T-cell lineage. Classically TCF-1 has been viewed as a downstream effector of the canonical WNT signaling pathway, bound by β-catenin in response to WNT activation to act as a transcriptional activator. However, TCF-1 has two main isoforms of which only the full-length protein (TCF-1p45) can interact with β-catenin, while the short isoform (TCF- 1p38) cannot. Therefore, TCF-1 can function within or independently of the WNT cascade. The direct binding of TCF-1 to its conserved motif bends the DNA helix and has the potential to alter the 3D chromatin conformation genome-wide with unknown consequences on the chromatin landscape, gene expression, and cellular development. Current evidence suggests that the functional outcomes of TCF-1 depends on the group of regulators with which it is co-recruited to DNA and on the presence or absence of the TCF-1 motif at the recruitment sites. Based on this evidence we postulate that TCF-1 regulates T cell development by binding to DNA in the context of discrete regulatory complexes to selectively shape the epigenetic landscape, 3D chromatin conformation, and gene expression of developing T cells. Optimally addressing this hypothesis without confounding developmental defects resulting from long-term TCF-1 deficiency requires inducible short-term manipulation of the protein levels of selective TCF-1 isoforms at specific stages of T cell development. Therefore, to study the molecular and epigenetic functions of TCF-1 in time and space, it is proposed to generate and validate three animal models that when combined allows the inducible, in vivo shortterm degradation of TCF-1 isoforms. One model will conditionally express the optimized version of the Oryza sativa TIR1 protein (OsTIR1(F74G), which enables precise temporal in vivo degradation of any mAID tagged protein in a tissue and developmental stage specific manner. The other two models will generate mAID tagged TCF-1p45 or all TCF-1 isoforms This research will not only offer crucial insight into longstanding questions of TCF1 functionality and the division of labor between its isoforms but will also provide novel validated mouse models as a resource to the wider community.


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 = $207,500 )
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$20,750
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	000	2	2/23/2024	NON-COMPETING CONTINUATION	$186,750
														Subtotal = $207,500

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	000	1	3/1/2023	NEW	$249,000
														Subtotal = $249,000

Grand Total All Awards = $456,500

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Tools for reversible short-term degradation of TCF-1 to address its molecular functions

Award Number: R21AI176254

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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