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Integration of Systems and Synthetic Biology to Advance Development of Human Tissues In Vitro

Award Number: R01DK139590
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: 09/30/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Integration of Systems and Synthetic Biology to Advance Development of Human Tissues In Vitro - Project summary/ abstract: Organoids reproduce the complex differentiation, cell sorting and self-organization of organogenesis, enabling the study of tissue development and modeling of organ physiology and disease ex vivo. The induced human Pluripotent stem cell (ihPSC) derived organoids are on their way to revolutionizing the future of human cell/organ transplantations. However, a major challenge is centered around the limited ability to control and direct the dynamic process of self-organization at the cellular population level. This drawback diminishes our engineering efforts to build reliable human tissues by mimicking natural biological processes. As such, currently, human organoids exhibit (a) aberrant cell types and (b) stalled developmental stages (immaturity) (c) limited robustness and reproducibility during multilineage tissue formation. In this proposal, we will harness the power of synthetic and system biology and provide a framework to build next-generation organoids with augmented performance and robustness for regenerative medicine. Our method is guided by computational models and genetic technologies. We have recently discovered that in our liver organoids, GATA6-engineered circuits can dictate final cell fates based on the initial GATA6 expression level. Here in Aim 1, we will establish a clonally resolved engineering approach to build human organoids. We will use our library of genetically engineered clones to rationally design mixtures of clones that exhibit specific quantitatively defined outcomes at the tissue level and use this to augment and reconstitute mesodermal niche important for liver maturation. The successful completion of this aim enables us to build human organoids with a high degree of reproducibility. In Aim 2, we devise a computational platform to design and build organoid variants with defined hepatic functions. The successful completion of this study will result in a hypothesis-driven framework for rational engineering and advancement of stem cell-derived tissues ex vivo. Our study will also generate liver tissues with close proximity to adult human liver and reduces dependence on animal experiments and increases access to refined human tissues.


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 = $596,431 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/13/2025	NON-COMPETING CONTINUATION	$596,431
														Subtotal = $596,431

Issue Date FY: 2024 ( Subtotal = $632,676 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$632,676
														Subtotal = $632,676

Grand Total All Awards = $1,229,107

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Integration of Systems and Synthetic Biology to Advance Development of Human Tissues In Vitro

Award Number: R01DK139590

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: 09/30/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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