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Principal Investigator: Ning Wang
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $323,319
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY
Poor sperm quantity and quality are major causes of male infertility, affecting ~7% of men worldwide. Male fertility
depends on the conversion of diploid germ cells (spermatogonia) into haploid spermatozoa (sperm). Meiotic
initiation, a defining step in this process, revolves around the transition from mitotic to meiotic cell cycles and
entails activation of meiotic genes required for the chromosomal events of meiosis prophase I. To date, a best
characterized gatekeeper of meiotic initiation in mammals is stimulated by retinoic acid gene 8 (Stra8), in that
Stra8P–/–P germ cells fail to express a subset of meiotic genes and do not enter meiosis. Our recent work indicates
a novel molecular role of STRA8 as a suppressor of autophagy, suggesting a novel link between meiotic initiation
and autophagy, a protein and cellular organelle degradation process. Based on this information, we hypothesize
that STRA8-mediated suppression of autophagy allows accumulation of proteins required for meiotic gene
activation and initiation; in the absence of STRA8, these proteins are degraded by autophagy, precluding meiosis.
To test our hypothesis, we will: 1) investigate the role of autophagy in STRA8-mediated meiotic initiation. 2)
define the molecular links between autophagy and meiotic initiation. Together, our study will establish autophagy
as a yet unrecognized regulator of meiotic initiation and uncover autophagy-sensitive proteins that serve as
essential molecular steps during this process in mammals. By developing a better understanding of autophagy
as a barrier to meiotic induction, our study will offer a significant technical advancement for in vitro gamete
production. Ultimately, translation of our study may identify novel therapeutic targets in the autophagy pathway
for male infertility or contraception treatment.
Terms: <ATRA><Affect><Alleles><Allelomorphs><Autophagocytosis><Basal Transcription Factor><Basal transcription factor genes><Binding><Cell Body><Cell Culture Techniques><Cell Cycle><Cell Division Cycle><Cell model><Cells><Cellular model><ChIP Sequencing><ChIP-seq><ChIPseq><Chromosomes><Contraception><Contraceptive methods><Data><Diploid><Diploidy><Event><Fertility Control><Gametes><Gatekeeping><Gene Activation><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Germ Cells><Germ-Line Cells><Haploid><Haploidy><In Vitro><Individual><Inhibition of Fertilization><Investigation><Investigators><Knowledge><Link><LoxP-flanked allele><Lysosomes><Male Contraception><Male Contraceptive Agents><Male Contraceptives><Male Infertility><Mammalia><Mammals><Mediating><Meiosis><Meiotic Prophase I><Mice><Mice Mammals><Mitotic><Molecular><Molecular Interaction><Murine><Mus><Organelles><Pathway interactions><Phenotype><Process><Production><Prophase I><Protein Degradation Induction><Proteins><Proteomics><Receptor Protein><Recycling><Reproductive Cells><Reproductive Medicine><Research><Research Personnel><Researchers><Resistance><Retinoic Acid><Role><Sex Cell><Sperm><Spermatocytes><Spermatogenesis><Spermatogenic Cell><Spermatogonia><Spermatophores><Spermatozoa><Spermiocytes><System><Techniques><Testing><Time><Trans Vitamin A Acid><Transactivation><Transcription Factor Proto-Oncogene><Transcription factor genes><Translations><Tretinoin><Tretinoinum><Vitamin A Acid><Work><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><all-trans-Retinoic Acid><all-trans-Vitamin A acid><autophagy><cell culture><cell cultures><chromatin immunoprecipitation-sequencing><floxed><floxed allele><gatekeeper><genetic approach><genetic strategy><homologous recombination><in vivo><inhibition of autophagy><inhibitor><initial cell><lead candidate><male antifertility drug><male fertility><male germ cells><meiotic><men><mutant><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><overexpress><overexpression><pathway><pharmacologic><prevent><preventing><promoter><promotor><receptor><resistant><sexual cell><shRNA><short hairpin RNA><small hairpin RNA><social role><sperm cell><spermatogone><spermatospore><spermigonium><spermospore><trans-Retinoic Acid><trans-activation><transcription factor><translation><zoosperm>