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Genetic Innovation of Cytoskeletal Proteins for Specialized Functions in the Male Germline

Award Number: R00GM137038
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Genetic Innovation of Cytoskeletal Proteins for Specialized Functions in the Male Germline - PROJECT SUMMARY Cytoskeletal proteins are fundamental in many biological processes among all eukaryotes. Given their essentiality, they are conventionally thought to be highly conserved. However, signatures of genetic innovation in the form of gene-family expansions and accelerated amino-acid substitutions are found among key cytoskeletal family members. Rapid molecular divergence between closely related species is unexpected in conserved protein families and is indicative of an adaptive advantage for sequence innovation. This proposal will investigate the causes and consequences of this dramatic diversification of cytoskeletal proteins. Actin- related proteins (Arps) are one cytoskeletal family that has ancient evolutionary origins yet exhibits recurrent genetic innovation in both mammals and insects. Unlike the well-conserved members of the Arp superfamily, divergent Arps are testis-specific in expression, suggesting they have acquired specialized roles for male reproduction. Yet the biological process that drives their innovation is unknown. The localization of gametic Arps in Drosophila suggests they play roles at germline-specific actin structures. This proposal will address the hypothesis that gametic Arps facilitate the generation of actin structures that are critical for male reproductive fitness. Aim 1 will uncover the function of one gametic Arp found in all Drosophila species, Arp53D, which localizes to two germline actin structures during late spermatogenesis. D. melanogaster, which has many well- established genetic tools and only one gametic Arp, provides an advantageous system in which to investigate the function of a divergent Arp at actin and probe how its structural diversification allows for novel roles. Aim 2 will extend the analysis to mammalian gametic Arps to gain a deeper understanding of the potentially shared biological processes that are driving Arp innovation among multiple phyla. A few pieces of evidence suggest that mammalian gametic Arps play actin regulatory roles, much like Arp53D. Aim 2 will take a comprehensive approach to elucidate their evolutionary histories and localization with respect to actin, while characterizing the male infertility phenotype of one Arp with an established mouse knockout model. Finally, preliminary findings suggest additional cases of rapidly evolving cytoskeletal proteins, beyond Arps, are present in the male germline. Aim 3 will systematically search Drosophila and mammalian genomes for rapid evolution and gene duplications among cytoskeletal proteins that are testis-enriched in expression. This aim will yield additional cases of genetic innovation that will serve as projects in the applicant’s future lab to broadly understand the adaptive sequence plasticity of cytoskeletal proteins and what drives their specialization for male reproduction. To launch this project, the applicant requires training in fertility assays, mouse testis histology and additional evolutionary analyses. She will ultimately use her background in biochemistry to study diversifying cytoskeletal proteins at a mechanistic level.


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 = $249,000 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	5	10/31/2023	NON-COMPETING CONTINUATION	$224,099
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	5	6/20/2024	NON-COMPETING CONTINUATION	$24,901
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	4	2/14/2023	NON-COMPETING CONTINUATION	$24,901
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	4	11/1/2022	NON-COMPETING CONTINUATION	$224,099
														Subtotal = $249,000

Issue Date FY: 2022 ( Subtotal = $313,595 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	3	12/3/2021	EXTENSION WITH OR WITHOUT FUNDS	$248,999
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	3	6/13/2022	EXTENSION WITH OR WITHOUT FUNDS	$64,596
														Subtotal = $313,595

Grand Total All Awards = $811,595

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Genetic Innovation of Cytoskeletal Proteins for Specialized Functions in the Male Germline

Award Number: R00GM137038

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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