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Coordinating the Developmental and Cell Cycle Programs of Spermatogenesis

协调精子发生的发育和细胞周期程序

基本信息

批准号：
8035560
负责人：
DIANE CAROL SHAKES
金额：
$ 27.95万
依托单位：
COLLEGE OF WILLIAM AND MARY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035560
关键词：
Address Affect Alleles Alzheimer&apos s Disease Apoptosis Biological Models Caenorhabditis elegans Cancerous Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Polarity Centrosome Chromosome Segregation Collection Complex Congenital Abnormality Coupled Defect Development Drug Delivery Systems Embryo Equipment Event Exhibits Female Fertility Gene Expression Genes Genetic Goals Homologous Gene Human Male Infertility Meiosis Microtubules Minor Molecular Morphogenesis Nature Nematoda Organism Parasitic nematode Pathology Pattern Phenotype Population Pregnancy loss Process Protein Binding Proteins RNA Interference RNA-Directed RNA Polymerase Research Infrastructure Research Personnel Role Small Interfering RNA Small RNA Spermatocytes Spermatogenesis Structure Temperature Work Yeasts cell motility cell transformation chromatin remodeling condensin mutant novel paralogous gene programs segregation sperm cell tau-tubulin kinase temperature sensitive mutant yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): To avoid apoptosis or cancerous transformations, cells within multi-cellular organisms must maintain a tight coordination between their cell cycle and differentiation programs. This challenge is particularly demanding for developing spermatocytes which must coordinate the complex process of meiotic chromosome segregation with a multi-faceted developmental program that includes the assembly of sperm-specific structures, the remodeling of chromatin into an initially quiescent yet ultimately totipotent state, and the subsequent acquisition of cell polarity and motility. In humans, defects in spermatogenesis are a major cause of male infertility, and minor defects in chromosome segregation, chromatin remodeling, or centrosome integrity are associated with pregnancy losses and birth defects. The long term goal of this project is to determine how the meiotic program of chromosome segregation is coordinated with the developmental (morphogenesis) program of spermatogenesis and whether specific defects in spermatogenesis are associated with predictable embryonic consequences. The numerous genetic, cytological, and molecular assets of the nematode C. elegans make it a powerful model system for investigating such questions and recent studies indicate that many spermatogenesis genes are conserved between worms and humans. The specific aims of this proposal are as follows: 1) Use a collection of cell cycle and cytological markers to analyze mutants with diverse defects in meiotic chromosome segregation and thus determine both the nature of their segregation defects and the extent to which various subprograms of the developmental program are affected, 2) Investigate the function of the novel spermatogenesis-specific gene, spe-7 by determining its dynamic sub-cellular localization pattern and identifying its protein binding partners, and 3) Explore whether sperm with different levels of centrosome and chromosome segregation abnormalities produce embryos with distinct and predictable defects. This project is well suited for involvement by undergraduate researchers, and the equipment will contribute to the research infrastructure of the department. PUBLIC HEALTH RELEVANCE: The proposed work is directly relevant to male infertility as it seeks to elucidate how the events of meiotic chromosome segregation are coordinated with the developmental events of spermatogenesis. It also seeks to establish C. elegans as a model system for addressing how defects in spermatogenesis contribute to pregnancy losses and birth defects. Lastly, the specific mutants selected for the purpose of analyzing meiotic chromosome segregation defects will also further our understanding of tau-tubulin kinase (a factor in the pathology of Alzheimer's), the role small RNAs in regulating gene expression, and a nematode-specific fertility protein which could potentially serve as a useful drug target against the various parasitic nematodes which infect more than one third of the world's population.

描述（由申请人提供）：为了避免细胞凋亡或癌性转化，多细胞生物体内的细胞必须在其细胞周期和分化程序之间保持紧密协调。这一挑战对于发育中的精母细胞尤其苛刻，精母细胞必须协调减数分裂染色体分离的复杂过程与多方面的发育程序，包括精子特异性结构的组装，染色质重塑为最初静止但最终全能状态，以及随后获得细胞极性和运动性。在人类中，精子发生缺陷是男性不育的主要原因，染色体分离、染色质重塑或中心体完整性的微小缺陷与妊娠损失和出生缺陷有关。该项目的长期目标是确定染色体分离的减数分裂程序如何与精子发生的发育（形态发生）程序协调，以及精子发生中的特定缺陷是否与可预测的胚胎后果相关。线虫C.线虫使其成为研究这些问题的一个强有力的模型系统，最近的研究表明，许多精子发生基因在蠕虫和人类之间是保守的。这项建议的具体目标如下：1）使用细胞周期和细胞学标记的集合来分析在减数分裂染色体分离中具有不同缺陷的突变体，从而确定它们的分离缺陷的性质和发育程序的各种子程序受影响的程度，2）研究新的精子发生特异性基因的功能，spe-7的动态亚细胞定位模式和蛋白质结合伴侣的鉴定; 3）探索具有不同水平的中心体和染色体分离异常的精子是否产生具有明显和可预测缺陷的胚胎。该项目非常适合本科研究人员的参与，设备将有助于该部门的研究基础设施。公共卫生相关性：拟议的工作是直接相关的男性不育，因为它试图阐明减数分裂染色体分离的事件是如何与精子发生的发育事件协调。它还试图建立C。线虫作为一个模型系统来解决精子发生缺陷如何导致妊娠损失和出生缺陷。最后，为了分析减数分裂染色体分离缺陷而选择的特定突变体也将进一步加深我们对tau-微管蛋白激酶（阿尔茨海默病病理学中的一个因素）、小RNA在调节基因表达中的作用以及线虫特异性生育蛋白的理解，所述线虫特异性生育蛋白可能作为有用的药物靶点来对抗感染超过三分之一世界人口的各种寄生线虫。