ADP-Ribose Polymer Metabolism in Spermatogenesis

精子发生中的 ADP-核糖聚合物代谢

• 批准号: 6968076
• 负责人: RALPH G MEYER
• 金额: $ 30.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968076
• 关键词: ADP ribosylation; DNA damage; DNA repair; adenosine diphosphate; cell differentiation; chromatin; enzyme mechanism; gene expression; genetically modified animals; glycosidases; laboratory mouse; nucleotide metabolism; pentosyltransferase; ribose; sperm; spermatogenesis

DESCRIPTION (provided by applicant): Chromatin integrity has been identified as an important prerequisite for normal sperm cell function. Incomplete chromatin condensation and the presence of persistent DMA strand breaks indicate a severe reduction of the fertilization potential in mature spermatozoa. These deficiencies can often result from faulty or incomplete execution of chromatin remodeling steps and DMA strand break management in immature steps of spermatid development. The objective of the proposed project is to identify basic functions of ADP-ribose (ADPR) polymer metabolism in germ cell differentiation that can be targeted for pharmacological intervention to prevent the persistence of residual DNA damage in germinal cells, particularly, but not limited to, men who have circumstantially been exposed to DNA damaging agents. The objective of the proposed project is to identify mechanisms of PARP-1, PARC and poly (ADP-ribose) function in postmeiotic germ cell maturation and to define the impact of ADP-ribose metabolism on the genetic and structural integrity of sperm cells. Based on our preliminary data, the central hypothesis for the proposed research is that ADPR polymer metabolism is required for efficient DNA strand break mediated chromatin reorganization during spermatid maturation. 3 specific aims are proposed: 1.) Determine parameters of mature sperm cell quality affected by ADPR polymer metabolism. 2.) Define the extent to which ADP-ribose polymer metabolism contributes to the repair of DNA strand breaks in spermatid nuclei. 3.) Identify target proteins of poly(ADP-ribosyl)ation in spermatid cells. The proposed investigations are expected to provide novel insights into the function of ADPR polymer metabolism in the maintenance of sperm cell quality. The project is innovative in its utilization of an interdisciplinary approach and the unique animal models that are involved. This research is significant because it is expected to contribute to the development of new therapeutic approaches that target ADPR polymer metabolism for the treatment of male fertility problems.

描述（由申请人提供）：染色质完整性已被确定为正常精子细胞功能的重要先决条件。不完整的染色质冷凝和持续的DMA链的存在表明，成熟精子中受精潜力的严重降低。这些缺陷通常可能是由于精子发育的未成熟步骤中的染色质重塑步骤和DMA链断压管理的故障或不完整的执行。拟议项目的目的是确定生殖细胞分化中ADP-核糖（ADPR）聚合物代谢的基本功能，该功能可以针对药理学干预，以防止生发细胞中残留DNA损伤的持久性，特别是尤其是限于与DNA损害患者经常暴露于DNA受损的男性。拟议项目的目的是确定PARP-1，PARC和聚（ADP-核糖）在症状后生殖细胞成熟中的功能，并定义ADP-核糖代谢对精子细胞遗传和结构完整性的影响。基于我们的初步数据，提出的研究的中心假设是ADPR聚合物代谢对于精子成熟过程中有效的DNA链断裂介导的染色质重组是必需的。提出了3个具体目的：1。）确定受ADPR聚合物代谢影响的成熟精子细胞质量的参数。 2.）定义ADP-核糖聚合物代谢在多大程度上有助于修复精子核中DNA链断裂的修复。 3.）鉴定精子细胞中聚（ADP-核糖基）的靶蛋白。拟议的研究有望提供有关ADPR聚合物代谢在维持精子细胞质量方面的功能的新见解。该项目在利用跨学科方法和所涉及的独特动物模型方面具有创新性。这项研究很重要，因为预计将有助于开发针对ADPR聚合物代谢的新治疗方法，以治疗男性生育问题。