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Synthetic organogenesis: new paradigms in reconstituting human organ development in vitro

Award Number: DP2HD108776
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Synthetic organogenesis: new paradigms in reconstituting human organ development in vitro - PROJECT SUMMARY Organogenesis is a process in which biochemical signals and mechanical cues transform embryonic germ layers into organs during fetal development. With recent advancements in stem cell biology, it has become possible to differentiate human pluripotent stem cells into expandable 3D tissues that contain many of the cellular and functional characteristics of fetal organs. These so-called organoids hold a tremendous potential to answer longstanding questions of human organogenesis and to one day serve as a renewable source of patient-specific human tissues. However, human organoids still only approximatively recapitulate organogenesis as they rely on spontaneous tissue self-organization and the establishment of signaling gradients in unpredictable ways. Furthermore, available organoid protocols focus on single organs and do not focus on morphogenesis. We be- lieve that making a meaningful progress in the field demands 1), gaining a deeper understanding of the coupling between signaling networks, tissue-specific transcriptional signatures, and tissue morphogenesis and 2), devel- oping novel cross-disciplinary tools that control spatiotemporal signaling to accurately mimic organogenesis in vitro. This proposal aims precisely to advance these gaps in our knowledge. We focus on the organogenesis of the gut tube, the embryonic structure on which many adjacent organs form, from thymus and lungs to the colon. Breaking away from the current organoid paradigms, which heavily rely on self-organization and the establish- ment of often uncontrolled internal gradients, we will combine tissue micropatterning and microfluidics to gen- erate precise signaling gradients so to reproducibly mimic both the signaling and the morphogenesis of gut tube organogenesis in vitro. Combined with live-cell microscopy, CRISPR editing, and single cell transcriptomics our organoids will reveal a detailed hierarchy of fate choices cells make from pluripotency to regionally specialized tissues in the gut tube, and they will allow us to make crucial connections between signaling, transcriptional regulation, and tissue morphogenesis. Our work will shed light on the largely unknown regulatory mechanisms by which the complex signaling pathways interact to create asymmetric patterns along the body axes. For the first time, our approach will recapitulate the formation of multiple adjacent gut tube progenitors from an em- bryonic germ layer, providing a unique window into one of longstanding questions in developmental biology: how do continuous signals create discretely separated organs along body axes? Finally, in collaboration with CRISPR experts, we will generate a pipeline that bypasses traditional morphogen-driven differentiation of plu- ripotent cells, but instead uses inducible genetic circuits to mimic fate decisions. This novel system will have the capacity to generate highly precise human tissues on the fly, in an approach that can be termed synthetic organ- ogenesis. Our proposed work will open routes to studying long elusive molecular mechanisms of early human organogenesis and start bridging the crucial gap between organoid biology and regenerative medicine.


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 = $0 )
2025	2021	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	3/13/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $948,236 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Child Health and Human Development Extramural Research	000	2	8/21/2024	EXTENSION WITH OR WITHOUT FUNDS	$948,236
														Subtotal = $948,236

Issue Date FY: 2022 ( Subtotal = $180,220 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	8/31/2022	SUPPLEMENT FOR EXPANSION	$180,220
														Subtotal = $180,220

Issue Date FY: 2021 ( Subtotal = $1,458,000 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	9/21/2021	NEW	$1,458,000
														Subtotal = $1,458,000

Grand Total All Awards = $2,586,456

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Synthetic organogenesis: new paradigms in reconstituting human organ development in vitro

Award Number: DP2HD108776

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/21/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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