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Decoding the Molecular Mechanisms Governing Regulation and Reprogramming of Cellular Identity

Award Number: R35GM153468
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: 03/05/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Decoding the Molecular Mechanisms Governing Regulation and Reprogramming of Cellular Identity - PROJECT SUMMARY The plasticity of cell identity is evident through nuclear transfer and transcription factor (TF)-mediated reprogramming. Despite this, current reprogramming methods often yield developmentally immature and heterogeneous cell populations and therefore are unsuitable for therapeutic application or disease modeling. We seek to address the fundamental questions of why direct reprogramming is inefficient, representing a critical gap in knowledge that will be widely applicable across many cell fate engineering strategies and has broader significance for understanding how cell identity is regulated. Over the past five years of NIGMS- supported research, we have developed and applied innovative single-cell multiomic lineage tracing and novel computational technologies to dissect the mechanisms of pioneer TF-mediated reprogramming. Our proposed research builds on this work, focusing on two primary objectives: 1. Current evidence supports the hypothesis that successful reprogramming events arise from rare 'reprogramming permissive' cell types or states in which normally inaccessible target genes are engaged by ectopic TFs to drive fate change. However, the lack of understanding about the origins of reprogramming presents a significant challenge in characterizing reprogramming permissive states. We will develop and apply multiomic lineage tracing to identify the origins of successfully reprogrammed cells across various cell fate conversion strategies. Elucidating reprogramming initiation mechanisms will identify new avenues to enhance reprogramming efficiency, uncovering common and cell-type specific regulation of cell identity. 2. The identification of new, more effective reprogramming cocktails represents a current gap in cell engineering. We hypothesize that expanded cocktails of precisely delivered TFs targeting the gene regulatory networks controlling terminal cell identity will more faithfully reprogram fate. However, it is currently experimentally and computationally intractable to predict these cocktails de novo. We will use cell fusion in combination with our genomic technologies to empirically deconstruct gene regulation, providing unique insights into efficient and accurate reprogramming, informing the development of novel TF cocktails. The outcomes of this research will have significant impacts on multiple levels: a) It will facilitate improved conversion efficiency and fidelity across different cell engineering strategies, overcoming a current barrier in regenerative medicine; b) The experimental manipulation of cell fate offers a valuable model system to deconstruct and model dynamic changes in cell identity. Our study of diverse reprogramming strategies will uncover general and cell type-specific rules for cell fate specification and maintenance, providing broad biological relevance beyond cell engineering; c) We will continue to develop our innovative genomic technologies, which provide insight into the regulation of cell identity across diverse cell biology paradigms.


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 = $403,650 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	2	1/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$403,650
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	003	2	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$289,477
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	002	1	4/25/2025	NEW	-$289,477
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	1	1/28/2025	NEW	$0
														Subtotal = $403,650

Issue Date FY: 2024 ( Subtotal = $390,305 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Biomedical Research and Research Training	000	1	3/5/2024	NEW	$390,305
														Subtotal = $390,305

Grand Total All Awards = $793,955

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Decoding the Molecular Mechanisms Governing Regulation and Reprogramming of Cellular Identity

Award Number: R35GM153468

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: 03/05/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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