Apoptotic dysregulation in male infertility

男性不育中的细胞凋亡失调

• 批准号: 10391711
• 负责人: Kaitlyn Ann Webster
• 金额: $ 3.43万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391711
• 关键词: Address; Adolescent; Adult; Advisory Committees; Affect; Age; Apoptosis; Apoptotic; Automobile Driving; BCL2 gene; Bax protein; Biological Assay; Biometry; Cell Cycle Stage; Cell Death; Cell Differentiation process; Cell Survival; Cell Transplantation; Cells; Cessation of life; Child; Continuing Education; Coupled; Couples; Cues; Data Analyses; Dependence; Development; Developmental Biology; Discipline; Disease; Disease model; Embryo; Embryonic Development; Endocrinology; Environmental Exposure; Epidemiology; Equilibrium; Etiology; Event; Excision; Experimental Designs; Exposure to; Faculty; Failure; Fellowship; Female; Fertility; Flow Cytometry; Genetic; Genetic Diseases; Genetic Models; Genitourinary system; Germ Cells; Goals; Gonadal Steroid Hormones; Gonadal structure; Histologic; Hormonal; Human; Image; Immunohistochemistry; Impairment; Incidence; Infertility; Inhibition of Apoptosis; Knock-out; Laboratories; Lead; Long-Term Effects; Maintenance; Male Infertility; Male Sterility; Mammals; Maps; Measures; Mediating; Mexican; Mitochondria; Modeling; Molecular Biology; Morphogenesis; Mus; Ovary; Pathway interactions; Phase; Physiological; Pituitary Gland; Process; Production; Protein Analysis; Protein Family; Proteins; Public Health; Public Health Schools; Quantitative Trait Loci; Recovery; Regulation; Reproductive Health; Reproductive Sciences; Research; Research Support; Research Training; Resistance; Sex Differentiation; Sexual Development; Signal Transduction; Spermatocytes; Spermatogenesis; Sterility; Structure; Structure of paramesonephric duct; Testing; Testis; Time; Tissues; Toxic Environmental Substances; Toxicant exposure; Training; VDAC1 gene; Zebrafish; beta catenin; bridge program; cancer therapy; cost; cytochrome c; cytotoxic; egg; environment related cancer; fertility preservation; fetal; hormonal signals; hypothalamic pituitary gonadal axis; insight; irradiation; male; male fertility; men; mullerian-inhibiting hormone; novel; predictive test; prepuberty; prevent; progenitor; regenerative; reproductive; reproductive outcome; reproductive tract; response; response to injury; responsible research conduct; sex; sex development disorder; spatiotemporal; sperm cell; stressor; toxicant

Project Summary/Abstract Across species, sexual development and fertility are dependent on cell death events. In developing ovaries and testes in mammals, massive death of germ cells (precursors of sperm and eggs) occurs during a fetal attrition event that is presumed to prevent overproliferation and select for highest quality cells. Cell death is also observed in males during embryonic regression of structures that form the female reproductive tract, and morphogenesis of the pituitary gland, which regulates gonadal sex hormone production. Surprisingly, inhibition of apoptosis results in male-specific infertility in mice, but it is not understood why this occurs or how cell death is regulated throughout male sexual development. The goal of my research is to understand regulation of apoptosis along the hypothalamic-pituitary-gonadal (HPG) axis throughout male sexual development, and why disruption of apoptosis causes infertility. Specifically, this proposal aims to map apoptotic sensitivity in normal testicular germ cells, and to find evidence of apoptotic misregulation in reproductive tissues in infertile males. In Aim 1, the apoptotic vulnerability of germ cells at different stages of development and differentiation will be determined using functional cell death-predictive assays and testicular irradiation to induce germ cell death. In Aim 2, the requirement of apoptosis in male sex differentiation will be investigated by analyzing embryonic reproductive tract development and adult HPG axis signaling in genetic models of apoptosis insufficiency. Testicular germ cell transplantation will be used to establish contribution of germline vs. somatic testicular cell apoptosis dysregulation to male infertility. These findings will support identification of targeted treatments for disorders of sexual development or cytotoxic exposures affecting developing children, which lead to poor reproductive outcomes as adults. The training plan for the proposed fellowship will further develop expertise in molecular and developmental biology approaches, and address conceptual and technical inexperience in other disciplines of reproductive science, including endocrinology and epidemiology. It will also provide the opportunity to move from zebrafish to mice as a model of disease and development. This will be achieved by continuing education in biostatistics, training with a co-sponsor, and utilizing an interdisciplinary scientific advisory committee to oversee experimental design and data analysis. Responsible conduct of research training will also be undertaken in Year 1. The Harvard School of Public Health, which is committed to the multi-faceted study of reproductive health and infertility, will strongly support this research and training plan with imaging and analytical facilities as well as oversight of established faculty in the field. The laboratory of Kristopher Sarosiek, which excels at functional assays of apoptosis, will enable development of a unique and rigorous research program that bridges sexual development and the molecular biology of cell death in order to uncover mechanisms driving male infertility.

项目总结/文摘