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Notch signaling regulates stem cell function in the fetal liver hematopoietic niche

Award Number: R01DK137093
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Notch signaling regulates stem cell function in the fetal liver hematopoietic niche - (PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Fetal liver hematopoietic stem cells (HSCs) are capable of rapid proliferation, robust functionality, and enhanced engraftment when used in a transplant setting. However, the complicated origins and migratory development of fetal HSCs have made their study difficult. It is not known why, and it has recently been debated if, fetal HSCs are superior to adult bone marrow HSCs. In previous studies, we have investigated the role of Notch signaling during fetal development where we have discovered a requirement for Notch1 in the viability and function of HSCs in the fetal liver (FL). We have also recently shown that the Notch ligand Jag1, expressed on hematopoietic cells, is required for function of FL HSCs. In this proposal, we will build on these findings to determine the mechanistic role of Notch signaling during expansion of fetal HSCs and how the fetal liver microenvironment sustains the growth, promotes the maturation and drives the functionality of definitive HSCs. Our preliminary findings indicate that multiple Notch receptors are expressed on FL HSCs and that Notch active cells are robust in engraftment and reconstitution after transplant. In Aim 1 we will leverage our discovery on reporter-based Notch activity to identify a sub-set of FL HSCs with enhanced functional potential. We hypothesize that Notch1 and Notch2 are active in the fetal liver, but that Notch1 activity is required for robust FL HSC activity. We will use in vivo transgenic animal models to conditionally delete Jag1 from specific fetal progenitors, myeloid and megakaryocytic cell types and will test functionality and visualize the FL niche that generates the most robust HSCs. Then, in Aim 2 we will extend our studies to identify novel factors that promote FL HSC expansion. We hypothesize that an antimicrobial family of secreted proteins are novel direct Notch target in FL HSCs, and that these cathelicidin peptides promotes FL HSC expansion. We will test this hypothesis by conditional transgenic deletion of novel target genes in hematopoietic cells and by supplementing the peptides in treatment of fetal, adult, and aged bone marrow HSCs. The knowledge gained from these aims will enhance our understanding of how microenvironmental signaling pathways during embryonic development drive stem cell expansion and function.


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: 2026 ( Subtotal = $320,660 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/23/2026	NON-COMPETING CONTINUATION	$320,660
														Subtotal = $320,660

Issue Date FY: 2025 ( Subtotal = $288,593 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/27/2025	NON-COMPETING CONTINUATION	$288,593
														Subtotal = $288,593

Issue Date FY: 2024 ( Subtotal = $319,800 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/28/2024	NEW	$319,800
														Subtotal = $319,800

Grand Total All Awards = $929,053

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Notch signaling regulates stem cell function in the fetal liver hematopoietic niche

Award Number: R01DK137093

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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