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Decoding the Molecular Mechanisms Underlying Reprogramming to Functional Hepatic and Intestinal Cell Types

Award Number: R01DK139580
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Decoding the Molecular Mechanisms Underlying Reprogramming to Functional Hepatic and Intestinal Cell Types - Recent advances in stem cell research over the past decade have sparked considerable interest in their therapeutic potential for treating gastrointestinal and hepatic disorders. By reprogramming somatic cells to pluripotency and differentiating them or directly reprogramming cells between somatic states via transcription factor (TF) overexpression, we can produce clinically valuable cells from abundant sources like skin fibroblasts. Despite its potential, direct reprogramming often leads to low yield and incomplete specification of target cells, limiting its practical use for therapy or disease modeling. Further, while many protocols to derive hepatocyte-like cells in mouse and human exist, there is a current unmet need to derive intestinal-like cells via reprogramming. Building on our previous five years of R01-funded research, we aim to answer why reprogramming is inefficient and how we can guide engineered cells toward a more defined identity and functionality. The conversion of mouse embryonic fibroblasts to induced endoderm progenitors (iEPs) represents a prototypical reprogramming strategy, producing cells that can functionally engraft the liver and intestine. Our work to date has demonstrated heterogeneity in this reprogramming process, revealing defined conversion trajectories to distinct cell populations. In our proposed research, we aim to; 1) Characterize reprogramming origin gene regulatory state, charting exogenous TF engagement in successful fate conversion. By understanding a) where ectopic TFs bind upon reprogramming initiation and b) the genetic regulatory barriers to this binding, we will reveal fundamental mechanistic knowledge that can be used to enhance the fidelity and efficiency of reprogramming; 2) Characterize hepatic and intestinal potential of iEPs. Our current data suggest that iEPs are a heterogeneous population of cells harboring hepatic and intestinal potential. By employing multiomic single-cell lineage tracing to characterize the heterogeneity of iEPs, we will track their successful engraftment into the liver and intestine to define their cellular potential. Further, we will track iEP differentiation within these target organs to establish a comprehensive blueprint for in vitro cell maturation; 3) Assess and optimize human direct reprogramming to induced endoderm progenitors. While many TF cocktails directing cells to hepatic identity have been reported, there is currently an unmet need to derive reprogrammed intestinal identities. Our preliminary data suggest that akin to mouse iEPs, human hepatocyte-like cells harbor intestinal identity. We hypothesize that the pioneer TF-based cocktails used in human reprogramming install this broad potential. By applying our innovative genomic technologies, we aim to unlock unforeseen potential in these engineered cells, paving the way to produce functional human liver and intestine cells through reprogramming.


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 = $566,790 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	4/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$566,790
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/16/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $566,790

Issue Date FY: 2024 ( Subtotal = $503,630 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/7/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$503,630
														Subtotal = $503,630

Grand Total All Awards = $1,070,420

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Decoding the Molecular Mechanisms Underlying Reprogramming to Functional Hepatic and Intestinal Cell Types

Award Number: R01DK139580

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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