Computer simulations of the mouse spermatogenic cycle

简介（由申请人提供）：不孕不育影响全球约7000万已婚夫妇；一半的病例归因于男性因素，其病因尚不清楚，治疗也极为有限。另一方面，由于可供男性选择的避孕药具很少，而且美国近一半的怀孕是意外的，因此需要新型的男性避孕药具。了解生精周期具有重要的临床意义，因为该过程的破坏会导致不育或生育能力低下，并且能够调节该过程将为男性避孕药提供新的途径。生精周期描述了睾丸组织中男性生殖细胞的周期性发育。周期的时空动态突出了生殖细胞和体细胞之间独特、复杂和相互依存的相互作用，是精子成功持续产生的关键。然而，导致睾丸组织模式出现的生殖细胞的确切作用仍未被描述。我们假设生殖细胞的周期性模式是由多种细胞行为引起的，包括反馈调节、有丝分裂和减数分裂、分化、凋亡和运动，遗传和环境扰动通过破坏这些细胞行为导致发育中的生殖细胞的排列改变。这个项目的目标是开发一个计算机模型，在数小时到数年的时间尺度上，在精管的横截面上模拟小鼠的生精周期。通过在计算机中单独或集体操纵细胞行为，该模型将允许我们预测睾丸形态正常和异常的因果事件。在此发布和生成的鼠标数据将用于开发我们的计算机模型并测试其预测能力。所提出的计算机模型将以延时电影的形式详细描述生殖细胞的时空动态，使我们能够追踪单个细胞的状态和位置变化。更重要的是，该模型提供了对男性生育基本原理的机械理解，即睾丸形态和连续精子生产是如何实现的。该项目的长期目标是将有关生殖系统动力学的知识整合到一个现实的计算机模型中，该模型包括在几分钟到几年的时间尺度上发生的分子、细胞和组织事件的空间尺度，并使用该模型确定不孕症治疗和避孕药开发的最佳方法。

DESCRIPTION (provided by applicant): Infertility affects ~70 million married couples around the world; half of the cases are attributed to male factors for which the cause is poorly understood and the treatment is extremely limited. On the other hand, novel male contraceptives are needed because very few options are available for males and nearly half of all pregnancies in the United States are unintended. Understanding the spermatogenic cycle has important clinical relevance, because disruption of the process leads to infertility or subfertility, and being able to regulate the process would provide new avenues to male contraceptives. The spermatogenic cycle describes the periodic development of male germ cells in the testicular tissue. The temporal-spatial dynamics of the cycle highlights the unique, complex, and interdependent interaction between germ and somatic cells, and is the key to successful continual production of sperm. However, the precise action of germ cells that leads to the emergence of testicular tissue patterns remains uncharacterized. We hypothesize that the periodic patterning of germ cells results from multiple cellular behaviors including feedback regulation, mitotic and meiotic division, differentiation, apoptosis, and movement, and that genetic and environmental perturbations cause the altered arrangement of the developing germ cells through disruption of these cellular behaviors. The goal of this project is to develop a computer model to simulate the mouse spermatogenic cycle on a cross-section of the seminiferous tubule over a time scale of hours to years. By manipulating cellular behaviors either individually or collectively in silico, the model will allow us to predict the causal eventsto the normal and abnormal testicular morphology. Mouse data, published and generated herein, will be used to develop our computer model and to test its predictive capabilities. The proposed computer model will elaborate the temporal-spatial dynamics of germ cells in a time-lapse movie format, allowing us to trace individual cells as they change state and location. More importantly, the model provides a mechanistic understanding of the fundamentals of male fertility, namely, how testicular morphology and continuous sperm production are achieved. The long-term goals of this project are to integrate knowledge about reproductive system dynamics into a realistic computer model that encompasses spatial scales of molecular, cellular, and tissue events occurring over a time scale of minutes to years and to use this model to identify optimal approaches for infertility treatment and contraceptive development.