Investigating The Functional Role Of Zinc Fluxes During Sperm Activation

 描述(申请人提供)：在美国，多达五分之一的夫妇寻求不孕不育治疗，其中男性不孕不育是报告的一半病例的主要原因。了解不孕症的分子基础仍然是寻找有效的生育治疗和选择的主要目标。一种新的理论认为，精浆中的低锌浓度是男性不育的潜在生理来源；然而，细胞内锌的作用尚未确定。O‘Halloran和Woodruff实验室最近发现，精子在获能过程中在精子头部和中段积累了3500万个锌原子，而在获能的前30分钟，不稳定的锌原子减少了大约50%。我们假设，精子激活期间细胞内锌浓度的波动在促进染色质紧凑和激活获能期间的蛋白酶活性方面是必不可少的。这个奖学金研究项目的目标是阐明 锌信号在精子获能过程中的作用和机制。这一目标将结合使用物理科学、化学和分子生物学的方法来实现。这一建议将决定(A)在获能过程中观察到的锌摄取是否是激活成功所必需的；以及(B)激活过程中锌对金属蛋白、蛋白酶活性和染色质紧致的分子机制。这项研究的结果将提供对精子中锌信号的新见解，这将有助于理解和开发男性不育的治疗方案。除了跨学科的研究 在化学和生殖科学双重导师的支持下，该奖学金将为跨学科培训和职业发展活动提供机会。这些遗嘱 包括参加广泛的专业会议、新的教学方法培训，以及参加西北大学研究生院主办的沟通技能讲习班和赠款撰写研讨会。此外，奖学金支持将使人们能够参加西北大学以外的专业发展活动，包括国家学术会议和实验室研讨会，如伍兹霍尔的生殖前沿。这项奖学金培训将使申请者在化学：生物方面的专业和学术表现出类拔萃。此外，这一奖学金将促进获得成功过渡到博士后研究员职位并最终成为一名独立的跨学科研究人员所需的知识和专业技能。

 DESCRIPTION (provided by applicant): In the United States, as many as one couple in five seeks infertility treatment, with male infertility being the leading cause of half the cases reportd. Understanding the molecular basis for infertility remains a major goal in the search for effective fertility treatments and options. An emerging theory identifies low zinc concentration in seminal plasma as a potential physical source of male infertility; however, the role of intracellular zinc has not yet been identified. The O'Halloran and Woodruff labs recently discovered that spermatozoa accumulate 35 million total zinc atoms to the sperm head and midpiece during capacitation while labile zinc decreases approximately 50% during the first 30 minutes of capacitation. We hypothesize that fluctuations in intracellular zinc concentrations that occur during sperm activation are essential in promoting chromatin compaction and activating protease activity during capacitation. The goal of this fellowship research project is to elucidate the role and mechanism of zinc signaling during sperm capacitation. This goal will be achieved using a combination of physical science, chemistry, and molecular biology approaches. This proposal will determine (a) if the zinc uptake observed during capacitation is essential for activation success; and (b) the molecular mechanism of zinc action during activation on metalloproteins, protease activity, and chromatin compaction. The outcome of this research will provide new insights into zinc signaling in spermatozoa that will aid in the understanding and development of treatment options for male infertility. In addition to an interdisciplinary research program supported by dual mentors in chemistry and reproductive science, this fellowship will provide an opportunity for transdisciplinary training and career development activities. These will include participation in a broad range of professional meetings, new training in teaching methods, and participation in communications skills workshops and grant writing seminars sponsored by The Graduate School at Northwestern. In addition, fellowship support will enable attendance at professional development events outside of Northwestern University, including national academic conferences and laboratory workshops, such as Frontiers in Reproduction at Woods Hole. This fellowship training will enable the applicant to excel professionally and academically at the chemistry:biology interface. In addition, this fellowship will foster an acquisition of the knowledge and professional skills necessary for a successful transition to a post-doctoral fellow position and ultimately as an independent transdisciplinary researcher.