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The Role of Chibby Family Members in Spermatogenesis and Male Fertility

Award Number: R01HD109232
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: 05/24/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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The Role of Chibby Family Members in Spermatogenesis and Male Fertility - PD/PI: Takemaru, Ken-Ichi 7. PROJECT SUMMARY Cilia are evolutionarily conserved microtubule-based structures that protrude from the apical cell surface to perform important biological functions, ranging from signal transduction to fluid movement. The sperm flagellum is a modified motile cilium that is essential for locomotion and fertilization of the egg. As such, abnormal sperm flagella are one of the leading causes of male infertility. Although not completely equivalent, analogous mechanisms are thought to operate during flagellogenesis and ciliogenesis. Defective ciliogenesis is associated with human disorders, known as ciliopathies, such as primary ciliary dyskinesia, and many of the male patients also show fertility issues. Despite worldwide research efforts to elucidate the role of ciliary proteins in these diseases, their physiological roles in male fertility remain poorly understood. We previously demonstrated that mice lacking the key ciliary protein Chibby1 (Cby1) exhibit ciliopathy phenotypes. Molecularly, Cby1 interacts with membrane-binding BAR domain proteins, called Cby1-interacting BAR domain-containing 1 and 2 (ciBAR1 and 2, formerly known as FAM92A and B), to facilitate ciliogenesis. More recently, we found that a Cby family member, Cby1-Like (Cby1L, also known as Cby3), is expressed abundantly and exclusively in the testis. Interestingly, Cby1L localizes to the annulus, a septin-based ring structure at the midpiece/principal piece (MP/PP) junction in the sperm tail, in the testis. To gain insight into the in vivo function of Cby1L during spermatogenesis, we created Cby1L-/- mice and found that male mice are completely infertile with the majority of sperm showing kinked tails around the MP/PP junction. Curiously, in the sperm from Cby1L-/- mice, the annulus is present but fails to stop at the MP/PP junction and progresses into the PP. Although the annulus is tightly bound to membranes during its migration, in Cby1L-/- testis, the annulus is partially detached from the flagellar membrane, suggesting that Cby1L is involved in anchoring the annulus to the membrane. Consistent with this hypothesis, we found that Cby1L physically interacts with ciBAR1 as well as the annulus septin SEPT4. Furthermore, we found that ciBAR1 localizes to the annulus, and ciBAR1-/- male mice are infertile, producing sperm with kinked tails. Collectively, our preliminary data suggest an exciting working model in which Cby1L in a complex with ciBAR1 stably anchors the annulus to flagellar membranes during its caudal migration and precisely positions it at the MP/PP junction likely via membrane shaping and constriction. The overall goal of this application is to understand the molecular roles of Cby1L and its binding proteins in spermatogenesis and male fertility. To achieve this goal, we propose the following Specific Aims: 1) Investigate the role of Cby1L in flagellogenesis using a Cby1L-/- mouse model; 2) Investigate the involvement of ciBAR1 in flagellogenesis and male fertility; and 3) Identify novel Cby1L-binding proteins and characterize their functions during flagellogenesis. We anticipate that our proposed research will unravel a novel mechanism underlying the proper compartmentalization of the sperm tail by ciliary proteins.


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: 2026 ( Subtotal = $428,508 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	4	1/15/2026	SUPPLEMENT FOR EXPANSION	$44,869
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	4	1/13/2026	NON-COMPETING CONTINUATION	$383,639
														Subtotal = $428,508

Issue Date FY: 2025 ( Subtotal = $503,182 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	3	1/24/2025	NON-COMPETING CONTINUATION	$383,639
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	3	4/24/2025	NON-COMPETING CONTINUATION	$42,626
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	004	3	8/17/2025	SUPPLEMENT FOR EXPANSION	$76,917
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	003	2	7/9/2025	OTHER REVISION	$0
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	002	2	4/25/2025	TERMINATION	$0
														Subtotal = $503,182

Issue Date FY: 2024 ( Subtotal = $445,327 )
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	002	2	8/21/2024	SUPPLEMENT FOR EXPANSION	$32,048
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	2	2/1/2024	NON-COMPETING CONTINUATION	$375,707
2024	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	2	5/6/2024	NON-COMPETING CONTINUATION	$37,572
														Subtotal = $445,327

Issue Date FY: 2023 ( Subtotal = $417,453 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	1	5/23/2023	NEW	$417,453
														Subtotal = $417,453

Grand Total All Awards = $1,794,470

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The Role of Chibby Family Members in Spermatogenesis and Male Fertility

Award Number: R01HD109232

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: 05/24/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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