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Transplantation of Testis Stem Cells in Large Animals

Award Number: R01OD016575
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2013
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Transplantation of Testis Stem Cells in Large Animals - Project Summary The long-term goals of this project are to establish germline stem cell (GSC)-based gene editing to generate large animal models of human diseases and for regenerative medicine (PAR-16-093), and to provide accessible systems to study the GSC niche in non-rodent animals. The testis stem cell is unique; it is the only cell type in an adult male that divides and contributes genes to future generations, making it an ideal target for genetic modification. Pigs are important models for pre-clinical research because they are phylogenetically and physiologically more similar to humans than rodents. Gene editing through GSCs rather than embryos will shorten the time necessary to produce germline gene edited animal models. It is also more broadly applicable to disease models where gene dosage and epigenetics have a role and smaller strains of pigs are required. The aims of this renewal project are 1) to establish a culture system that promotes porcine germ cell expansion in vitro; 2) to explore the role of testicular somatic cells in formation of a functional GSC niche; and 3) to develop a precise approach for targeted gene editing in porcine GSCs. While germline transmission of a genetic modification is possible with transplantation of primary pGSCs, efficiency of the approach would benefit from a robust in vitro system for expansion of edited cells prior to transplantation. To accomplish this goal, we will define the metabolic phenotype of pGSCs to inform design of appropriate culture conditions. Grafting to mouse hosts and transplantation to recipient pigs will monitor the ability of cultured cells to support spermatogenesis as functional endpoint. Germ cell function is controlled by interaction with the niche microenvironment. Our novel testicular organoid system and xenografting of testis cells will enable introduction of cell type-specific modifications and characterize stem cell-niche interactions. We will test the hypothesis that primary cilia on testicular somatic cells are essential for niche formation, and that the somatic environment modulates germ cell differentiation and supports germ lineage differentiation of porcine induced pluripotent stem cells (piPSCs). Finally, we will test the hypothesis that CRISPR/Cas9 ribonucleoprotein (RNP)-mediated homology directed repair (HDR) will allow efficient targeted genome editing in GSCs for precise replication of human disease alleles. As HDR is limited to small DNA alterations (~1-50 bp), we will also explore Precise Integration into Target Chromosome (PITCh) for targeted gene editing to enable introduction of large transgenes and/or humanizing parts of the pig genome for regenerative medicine. Introduction of a mutant porcine insulin gene (INSC94Y) that matches the human INSC96Y mutation present in permanent neonatal diabetes mellitus will provide proof-of-principle that our novel strategies are feasible and efficient. Overall, this work will establish precise targeted germline gene editing in pigs, and further define stem cell-niche interactions.


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: 2024 ( Subtotal = $239,058 )
2024	2024	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB			CAN	Research Infrastructure Programs	001	21	5/17/2024	NON-COMPETING CONTINUATION	$47,812
2024	2024	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB			CAN	Research Infrastructure Programs	000	21	1/31/2024	NON-COMPETING CONTINUATION	$191,246
														Subtotal = $239,058

Issue Date FY: 2023 ( Subtotal = $239,058 )
2023	2023	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB			CAN	Research Infrastructure Programs	000	20	2/18/2023	NON-COMPETING CONTINUATION	$239,058
														Subtotal = $239,058

Issue Date FY: 2022 ( Subtotal = $239,058 )
2022	2022	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB			CAN	Research Infrastructure Programs	001	19	5/17/2022	NON-COMPETING CONTINUATION	$23,905
2022	2022	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB			CAN	Research Infrastructure Programs	000	19	2/9/2022	NON-COMPETING CONTINUATION	$215,153
														Subtotal = $239,058

Issue Date FY: 2021 ( Subtotal = $239,058 )
2021	2021	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB			CAN	Research Infrastructure Programs	000	18	2/23/2021	NON-COMPETING CONTINUATION	$239,058
														Subtotal = $239,058

Issue Date FY: 2020 ( Subtotal = $239,058 )
2020	2020	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB	T2N 1N4		CAN	Research Infrastructure Programs	003	17	4/23/2020	COMPETING CONTINUATION	$34,153
2020	2020	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB	T2N 1N4		CAN	Research Infrastructure Programs	002	17	3/6/2020	COMPETING CONTINUATION	$204,905
2020	2017	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB	T2N 1N4		CAN	Research Infrastructure Programs	000	16	1/23/2020	NON-COMPETING CONTINUATION	$0
2020	2017	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB	T2N 1N4		CAN	Research Infrastructure Programs	001	16	3/5/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $239,058

Issue Date FY: 2017 ( Subtotal = $227,673 )
2017	2017	GOVERNORS OF THE UNIVERSITY OF CALGARY, THE	2500 UNIVERSITY DR NW	CALGARY	AB	T2N 1N4		CAN	Research Infrastructure Programs	000	16	8/21/2017	NON-COMPETING CONTINUATION	$227,673
														Subtotal = $227,673

Issue Date FY: 2016 ( Subtotal = $238,207 )
2016	2016	UNIVERSITY OF CALGARY	**	CALGARY, ALBERTA				CAN	Research Infrastructure Programs	000	15	8/9/2016	NON-COMPETING CONTINUATION	$238,207
														Subtotal = $238,207

Issue Date FY: 2015 ( Subtotal = $228,870 )
2015	2015	UNIVERSITY OF CALGARY	**	CALGARY, ALBERTA				CAN	Research Infrastructure Programs	000	14	8/7/2015	NON-COMPETING CONTINUATION	$228,870
														Subtotal = $228,870

Issue Date FY: 2014 ( Subtotal = $237,252 )
2014	2014	UNIVERSITY OF CALGARY	**	CALGARY, ALBERTA				CAN	Research Infrastructure Programs	000	13	8/29/2014	NON-COMPETING CONTINUATION	$237,252
														Subtotal = $237,252

Issue Date FY: 2013 ( Subtotal = $231,618 )
2013	2013	UNIVERSITY OF CALGARY	2500 UNIVERSITY DR NW	CALGARY, ALBERTA				CAN	Research Infrastructure Programs	000	12	7/4/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$231,618
														Subtotal = $231,618

Grand Total All Awards = $2,358,910

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Transplantation of Testis Stem Cells in Large Animals

Award Number: R01OD016575

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2013

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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