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Intraflagellar transport (IFT) and sperm formation

Award Number: R01HD105944
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: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Intraflagellar transport (IFT) and sperm formation - Summary Intraflagellar transport (IFT) is an evolutionarily conserved mechanism for cilia formation. Defects in IFT/cilia have been linked to cilia-related diseases. Although the roles of IFT in somatic tissues have been extensively studied, little is known about its role in sperm flagella formation, which are specialized motile cilia with accessory structures. Using conditional knockout (cKO) strategies, our laboratory analyzed male germ cell- specific IFT mutant mice and discovered that all the analyzed IFTs are required for normal sperm formation/function. Among the Ift genes, Ift25 and Ift27 hold particular interest. The two IFTs form a heterodimer through their unique characterized structures. Although these two genes are not required for cilia assembly in somatic cells, both are essential for sperm formation and function. Specific elimination of each of these genes in male germ cells resulted in almost identical sterile phenotypes. Sperm from these mice were immotile and had disorganized accessory structures, especially the fibrous sheath. Levels of testicular pro- AKAP4, the precursor protein of AKAP4, an A-kinase anchor protein (AKAP) and significant component of the sperm fibrous sheath, were increased; on the contrary, the mature AKAP4 was significantly reduced in both Ift25 and Ift27 cKO mice. IFT25 associates with dynactin 4 (DCTN4), a dynein-associated protein. In addition to IFT25, IFT27 also associates with signal peptide peptidases like 2a (SPPL2a), which functions as a protease and is present in developing sperm flagella. The formation of mature AKAP4 was also affected in the Sppl2a KO mice. Based on these observations, we propose the following central hypotheses: 1 ) IFT25 and IFT27 are dedicated to the movement and placement of accessory structure components critical for functional sperm, and 2) The IFT25/IFT27 complex use specific domains to form IFT complex particles for sperm flagella assembling. To test these hypotheses, we propose the following Specific Aims: 1. To characterize the IFT25/IFT27 complex components in the testis essential for normal sperm morphogenesis, particularly the formation of accessory structures; 2. To investigate sperm accessory structure defects of Ift25 cKO mice dynamically and develop an in vivo system to track the IFT25 complex trafficking in live germ cells for sperm flagella assembly; and 3. To explore functional consequences of IFT25/27 disruption in sperm signaling. We propose that the IFT25/IFT27 heterodimer forms a transporting complex containing SPPL2a and DCTN4 through specific domains in male germ cells for normal sperm accessory structure assembly; we expect defects in accessory structures in the Ift25 cKO mice will occur at specific developmental steps. The dynamic trafficking process of the IFT25 complex in live male germ cells can be tracked. We hypothesize that SPPL2a is involved in processing pro-AKAP4 to mature into AKAP4, resulting in normal PKA signaling in mature sperm. The proposed research will elucidate the mechanisms of the two IFT proteins in the formation of functional sperm and build a platform to study the roles of other IFT components in male and female reproduction. .


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 = $531,517 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Child Health and Human Development Extramural Research	000	4	2/12/2025	NON-COMPETING CONTINUATION	$478,365
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Child Health and Human Development Extramural Research	001	4	8/26/2025	NON-COMPETING CONTINUATION	$53,152
														Subtotal = $531,517

Issue Date FY: 2024 ( Subtotal = $490,340 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Child Health and Human Development Extramural Research	000	3	1/25/2024	NON-COMPETING CONTINUATION	$445,762
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Child Health and Human Development Extramural Research	001	3	5/16/2024	NON-COMPETING CONTINUATION	$44,578
														Subtotal = $490,340

Issue Date FY: 2023 ( Subtotal = $436,910 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Child Health and Human Development Extramural Research	000	2	2/15/2023	NON-COMPETING CONTINUATION	$436,910
														Subtotal = $436,910

Issue Date FY: 2022 ( Subtotal = $405,306 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Child Health and Human Development Extramural Research	000	1	3/23/2022	NEW	$405,306
														Subtotal = $405,306

Grand Total All Awards = $1,864,073

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Intraflagellar transport (IFT) and sperm formation

Award Number: R01HD105944

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: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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