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A knock-in mouse model for male fertility: basis for the mammal-specific protein phosphatase isoform PP1y2 in sperm

Award Number: R03HD107333
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: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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A knock-in mouse model for male fertility: basis for the mammal-specific protein phosphatase isoform PP1y2 in sperm - Spermatogenesis and the development of fertility competent sperm involve complex processes in the testis, epididymis and female reproductive tract. These physiological processes of sperm formation and development are difficult if not impossible to be recapitulated and studied in vitro. Mouse models amenable to genetic manipulation are essential for understanding the basis for male gamete function. Considerable progress has been made in identifying signaling proteins essential for sperm function which include components of cyclic AMP metabolism, proteins controlling sperm intracellular pH and calcium levels of sperm in the epididymis and in the female reproductive tract. Numerous gene knock out approaches targeting the signaling proteins involved in metabolism and in the action of second messengers result in male infertility. Yet the mechanistic basis for normal and disrupted sperm function remains largely unknown. We discovered that a protein phosphatase PP12, which is one of two paralogs from one gene Ppp1cc, is highly expressed in testis and present in sperm. The other paralog, PP11, is expressed in brain and several somatic cells and tissues and cells. Two other genes encode the PP1 and PP1 isoforms. These four PP1 isoforms are highly conserved between themselves and across species. The isoform PP12 is present only in placental mammals suggesting an essential role for it in the unique features of mammalian sperm function. It is notable that sperm from other species contain one of the protein phosphate isoforms PP11, PP1 or PP1. The targeted knock out of Ppp1cc results in male infertility. Transgenic expression of PP12, but not PP11, driven by a testis specific promoter restores fertility in the Ppp1cc null mice, highlighting the essential requirement for PP12. In this proposal we will examine a mouse line we have generated where the Ppp1cc gene is edited by Crispr/Cas9 to express PP11 alone in testis. Determination of the impaired functions in PP11 bearing mice and sperm should lead to the identification of key proteins essential for normal sperm function. Male infertility is responsible for about 10% of infertile couples. Identification of the causes and treatments for male infertility are limited. A number of factors can affect male infertility: major factors are likely environmental or genetic. This mouse model bearing the non-mammalian PP1 isoform in sperm should also be valuable in not only understanding the significance of the presence of PP12 in all mammals but also in understanding the biochemical basis for fertility and infertility in man.


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	2023	KENT STATE UNIVERSITY	1500 HORNING RD	KENT	OH	44242	PORTAGE	USA	Child Health and Human Development Extramural Research	000	2	7/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $76,000 )
2023	2023	KENT STATE UNIVERSITY	1500 HORNING RD	KENT	OH	44242	PORTAGE	USA	Child Health and Human Development Extramural Research	000	2	8/8/2023	NON-COMPETING CONTINUATION	$76,000
														Subtotal = $76,000

Issue Date FY: 2022 ( Subtotal = $76,000 )
2022	2022	KENT STATE UNIVERSITY	1500 HORNING RD	KENT	OH	44242	PORTAGE	USA	Child Health and Human Development Extramural Research	000	1	8/1/2022	NEW	$76,000
														Subtotal = $76,000

Grand Total All Awards = $152,000

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A knock-in mouse model for male fertility: basis for the mammal-specific protein phosphatase isoform PP1y2 in sperm

Award Number: R03HD107333

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: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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