Adenine Nucleotide Metabolism and Signaling in Mammalian Sperm

描述（申请人提供）：人类生殖医学的进步需要对配子蛋白的结构和功能有深入的了解。在我们最近对小鼠精子尾部附属结构的蛋白质组学分析中，我们证明了鞭毛中存在腺嘌呤核苷酸代谢的重要酶。除了基本的精子运动，关键的精子功能，如获能和超激活的运动依赖于使用腺嘌呤核苷酸作为能量来源和信号分子。然而，将腺嘌呤核苷酸整合到精子中各种合成、降解和信号传导途径中的机制尚不清楚。因此，这个项目广泛的、长期的目标是确定ATP、ADP和AMP的相对作用如何影响精子活力。我们提出，精子鞭毛特定区域的腺苷酸能量电荷通过ATP提供的能量，并通过ATP、ADP和AMP介导的信号调节，影响每个微环境中运动的质量和活力。为了解决这些问题，我们提出了三个具体目标。目的1是确定腺苷酸激酶是如何通过ADP与ATP + AMP的相互转化来调节精子活力的。要验证的假设是，给定精子细胞内的腺苷酸能量电荷会影响精子活力的质量，并成为与过度激活相关的变化的基础。目的二是鉴定精子的AK蛋白和与之相互作用的鞭毛蛋白。要验证的假设是精子ak与鞭毛的其他蛋白质形成调节复合物。目的3是确定AMP调节精子运动的调控途径。要验证的假设是，amp敏感酶是精子生理的重要调节因子。我们提出腺嘌呤核苷酸作为主要能量储存（ATP）、补充能量（ADP）和能量测量（AMP）调节精子代谢和运动的多重作用。公共卫生相关性：精子必须有适当的运动才能使卵子受精。了解腺嘌呤核苷酸在调节精子鞭毛的速率、振幅和波形中的作用，可能为不育夫妇提供新的帮助，并开发新的避孕方法。从这些研究中获得的信息可能有助于了解涉及鞭毛的全球重要疾病/感染（例如多囊肾病、锥虫病）。

DESCRIPTION (provided by applicant): Advances in human reproductive medicine require in-depth knowledge about the structure and function of gamete proteins. In our recent proteomic analysis of the accessory structures of mouse sperm tails, we demonstrated that important enzymes of adenine nucleotide metabolism are present in the flagellum. Besides basal sperm motility, key sperm functions such as capacitation and hyperactivated motility rely on the use of adenine nucleotides as energy sources and as signaling molecules. However, the mechanisms integrating adenine nucleotides into various pathways of synthesis, degradation, and signaling in sperm are poorly understood. Thus, the broad, long-term goal of this project is to determine how the relative roles of ATP, ADP, and AMP influence sperm motility. We propose that the adenylate energy charge in a given region of the sperm flagellum impacts the quality and vigor of movement in each microenvironment through the energy provided by ATP and modulated by signaling mediated via ATP, ADP, and AMP. To address these issues, we propose three specific aims. Aim 1 is to determine how sperm motility is regulated by adenylate kinase through the interconversion of ADP to ATP plus AMP. The hypothesis to be tested is that the adenylate energy charge within a given sperm cell affects the quality of motility and underlies the changes associated with hyperactivation. Aim 2 is to Identify AK proteins of sperm and the flagellar proteins that interact with them. The hypothesisto be tested is that sperm AKs form regulatory complexes with other proteins of the flagellum. Aim 3 is to determine the regulatory pathway(s) utilized by AMP to modify sperm motility. The hypothesis to be tested is that AMP-sensitive enzymes are important regulators of sperm physiology. We propose that adenine nucleotides serve multiple roles as primary energy stores (ATP), supplemental energy (ADP), and energy gauge (AMP) to regulate sperm metabolism and motility. PUBLIC HEALTH RELEVANCE: Sperm must have proper motility to fertilize an egg. Understanding the roles of adenine nucleotides in regulating the rate, amplitude, and waveforms of the sperm flagellum may provide new ways to assist couples experiencing infertility and to develop new forms of contraception. Information gained from these studies may aid in the understanding of globally important diseases/infections involving flagella (e.g., polycystic kidney disease, trypanosomes).