Insight into the physiological architecture of seminiferous tubule Ca2+ signaling

尽管受精具有重要的生物学作用，但对控制生精周期的生理学原理仍缺乏概念性的机械理解。因此，我研究的长期目标是深入了解协调精子发生的终生大量增殖和分化过程的分子和细胞机制。在这个提案中，我将重点放在大多数细胞信号通路的一个关键组成部分--钙离子--并旨在揭示这种通用的信使分子在睾丸(病理)生理学中的作用。在生精上皮中，关于Ca~(2+)信号及其在生精周期中的作用的知识相当零散。虽然已经证明FSH和睾酮对精子发生的内分泌控制在功能上会聚在支持细胞的钙动员上，但其潜在的机制仍然不清楚。建立在未发表的先导研究和创新方法论的坚实基础上，我提出了一个综合的多方面研究策略，(I)分别针对Sertoli细胞和生殖细胞中的自发钙信号，(Ii)旨在解决作为动物内分泌状态函数的此类信号的动态变化。这一提议的一个显著特点是将成熟的神经生物学方法，如脑切片生理学和多光子活体成像，转移到生殖生物学领域。我坚信，采用这种跨学科的方法将为最神秘的生理过程之一--精子发生提供丰富的令人兴奋的新信息。

Despite the essential biological role of fertilization, a conceptual mechanistic understanding of the physiological principles that control the spermatogenic cycle is still lacking. Therefore, the long-term goal of my research is to gain insight into the molecular and cellular mechanisms that orchestrate the life-long mass proliferation and differentiation process of spermatogenesis. In this proposal, I focus on a critical component of most cellular signaling pathways – Ca2+ – and aim to unravel the role of this universal messenger molecule in testicular (patho)physiology. In the seminiferous epithelium, knowledge about Ca2+ signaling and its role in the spermatogenic cycle is rather fragmentary. While it has been demonstrated that endocrine control of spermatogenesis by both FSH and testosterone functionally converges on Ca2+ mobilization in Sertoli cells, the underlying mechanisms remain elusive. Built on a solid foundation of unpublished pilot research and innovative methodology, I propose an integrated multi-faceted research strategy that (i) targets spontaneous Ca2+ signals in Sertoli and germ cells, respectively, and that (ii) aims to address the dynamic profile of such signals as a function of an animal’s endocrine state. A distinctive feature of this proposal is the transfer of well-established neurobiological methodology, such as brain slice physiology and multi-photon in vivo imaging, to the field of reproductive biology. I firmly believe that adoption of this trans-disciplinary approach will provide a wealth of exciting novel information on one of the most enigmatic physiological processes – spermatogenesis.