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Award Abstract # 2134999
Collaborative Research: RECODE: Directed Differentiation of Human Liver Organoids via Computational Analysis and Engineering of Gene Regulatory Networks

NSF Org: CBET
Division of Chemical, Bioengineering, Environmental, and Transport Systems
Recipient: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
Initial Amendment Date: July 29, 2021
Latest Amendment Date: July 29, 2021
Award Number: 2134999
Award Instrument: Standard Grant
Program Manager: Steve Zehnder
szehnder@nsf.gov
 (703)292-7014
CBET
 Division of Chemical, Bioengineering, Environmental, and Transport Systems
ENG
 Directorate for Engineering
Start Date: January 1, 2022
End Date: December 31, 2025 (Estimated)
Total Intended Award Amount: $1,064,877.00
Total Awarded Amount to Date: $1,064,877.00
Funds Obligated to Date: FY 2021 = $1,064,877.00
History of Investigator:
  • Mo Ebrahimkhani (Principal Investigator)
    mo.ebr@pitt.edu
  • Samira Kiani (Co-Principal Investigator)
Recipient Sponsored Research Office: University of Pittsburgh
4200 FIFTH AVENUE
PITTSBURGH
PA  US  15260-0001
(412)624-7400
Sponsor Congressional District: 12
Primary Place of Performance: University of Pittsburgh
300 MURDC, 3420 Forbes Avenue
Pittsburgh
PA  US  15213-3202
Primary Place of Performance
Congressional District:
12
Unique Entity Identifier (UEI): MKAGLD59JRL1
Parent UEI:
NSF Program(s): RECODE,
Systems and Synthetic Biology
Primary Program Source: 01002122DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 1757, 7465
Program Element Code(s): 171Y00, 801100
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.041

ABSTRACT

Organoids are group of cells produced from stem cells that mimic closely structure and functions of human organs. Organoids can be used for modeling the development of human diseases and for testing newly produced medicines. However, there is a need for generation of human organoids with better function and less variability. This project aims to use genetic based analysis and engineering to control stem cell differentiation towards human liver cells and improve the final manufacturing outcome of liver organoids. As part of the activities in this project, graduate and undergraduate students will be trained and short educational video clips will be made for online education and public engagement.

This RECODE project will address biotechnology challenges of in vitro liver organoid engineering such as maturity, vascular formation, and reproducibility. To this end, synthetic biology, stem cell engineering, and systems biology will be integrated to develop a platform for autonomous differentiation of human induced pluripotent stem cells to liver organoids. Studies will be performed in two independent objectives to: 1) develop synthetic gene circuits for multistep differentiation in liver organoids and 2) identify lineage plasticity regulators during differentiation to control final cell fates in engineered organoids. The understanding gained through this work will address knowledge gaps applicable to cellular differentiation, human liver maturation, and vascular formation. This project will also provide support for the development of a strong STEM workforce through novel online education and public outreach activities surrounding stem cell engineering.

This RECODE award is co-funded by the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biosciences and the Engineering Biology and Health Cluster in the Division of Chemical, Bioengineering, Environmental, and Transport Systems.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Hislop, Joshua and Song, Qi and Keshavarz_F, Kamyar and Alavi, Amir and Schoenberger, Rayna and LeGraw, Ryan and Velazquez, Jeremy J and Mokhtari, Tahere and Taheri, Mohammad Naser and Rytel, Matthew and Chuva_de_Sousa_Lopes, Susana M and Watkins, Simon a "Modelling post-implantation human development to yolk sac blood emergence" Nature , v.626 , 2024 https://doi.org/10.1038/s41586-023-06914-8 Citation Details
Lo, Emily KW and Velazquez, Jeremy J and Peng, Da and Kwon, Chulan and Ebrahimkhani, Mo R and Cahan, Patrick "Platform-agnostic CellNet enables cross-study analysis of cell fate engineering protocols" Stem Cell Reports , v.18 , 2023 https://doi.org/10.1016/j.stemcr.2023.06.008 Citation Details
Maggiore, Joseph C and LeGraw, Ryan and Przepiorski, Aneta and Velazquez, Jeremy and Chaney, Christopher and Vanichapol, Thitinee and Streeter, Evan and Almuallim, Zainab and Oda, Akira and Chiba, Takuto and Silva-Barbosa, Anne and Franks, Jonathan and Hi "A genetically inducible endothelial niche enables vascularization of human kidney organoids with multilineage maturation and emergence of renin expressing cells" Kidney International , v.106 , 2024 https://doi.org/10.1016/j.kint.2024.05.026 Citation Details
Shafritz, David A and Ebrahimkhani, Mo R and Oertel, Michael "Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues" Cells , v.12 , 2023 https://doi.org/10.3390/cells12040529 Citation Details

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