Spatial, temporal and environmental regulation of early gonadogenesis in C. elegans

 描述（由申请人提供）：C。线虫是研究发育生物学中与人类发育和疾病普遍相关的基本问题的首要模式生物。该基金的总体目标是研究空间，时间和环境对C。优雅C.线虫是一种实验上易于处理的模型，用于研究器官发生的机制和信号事件。我们将使用强大的方法进行遗传分析，实时成像，分子操作和基因组工程，以实现三个具体目标。 其中两个目标是与空间模式有关，涉及早期性腺发生中Notch介导的细胞-细胞相互作用。我们将研究随机过程如何产生由LIN-12/Notch信号传导解决的发育等效细胞之间的差异，以及Notch信号传导需求的不对称性如何产生并有助于细胞命运多样化。这些目标的基础生物学与理解干细胞的细胞动力学、生物体发育和体内组织稳态的维持高度相关;具有潜在治疗应用的细胞命运重编程离体;以及癌症生物学。我们所了解的Notch信号传导和细胞命运多样化的机制将直接适用于正常发育中的其他环境，并且由于异常的Notch活性与许多不同的癌症以及发育，免疫和神经系统疾病有关，因此拟议的工作对人类健康和疾病有许多影响。 我们还将研究如何在不同的环境条件下控制性腺发生过程中的细胞和形态发生事件的时间进展。特别地，我们将研究细胞静止的调节，细胞已经退出细胞周期但仍保持静止的状态。 在性腺发育的早期能够重新进入它。静止是一种基本的细胞特性，它使干细胞能够随着时间的推移而持续存在，而不会失去发育潜力。在第三个目标中，我们将研究时间和环境信息如何控制进入和出现从静止的性腺母细胞。发育进程的环境调节利用高度保守的胰岛素信号传导途径，因此研究环境如何影响早期性腺发生可能与流行的人类疾病（包括糖尿病和肥胖症）相关。 总而言之，这项工作对基础人类发育生物学以及人类健康和疾病具有许多意义。通过这些研究，我们将更深入地了解发育机制，这将可能适用于开发人类疾病的诊断和治疗工具，这是NIH的中心使命。

 DESCRIPTION (provided by applicant): C. elegans is a premier model organism for studying basic questions in development biology of general relevance to human development and disease. The overall goal of this grant is to investigate spatial, temporal and environmental regulation of early gonadogenesis in C. elegans. The somatic gonad of C. elegans is an experimentally tractable model for studying mechanisms and signaling events underlying organogenesis. We will use powerful methods for genetic analysis, live imaging, molecular manipulation and genome engineering to achieve three specific aims. Two of the aims are concerned with spatial patterning involving Notch-mediated cell-cell interactions in early gonadogenesis. We will study how stochastic processes generate differences between developmentally equivalent cells that are resolved by LIN-12/Notch signaling, and how an asymmetry in the requirement for Notch signaling is generated and contributes to cell fate diversification. The basic biology of these aims is highly relevant to understanding the cellular dynamics underlying stem cells, organismal development, and the maintenance of tissue homeostasis in vivo; cell fate reprogramming with potential therapeutic applications ex vivo; and cancer biology. What we learn about Notch signaling and mechanisms to diversify cell fate will be directly applicable to other contexts in normal development and, since aberrant Notch activity has been implicated in many different cancers and in developmental, immune, and neurological disorders, the proposed work has many implications for human health and disease. We will also investigate how temporal progression of cellular and morphogenetic events during gonadogenesis is controlled under different environmental conditions. In particular, we will study the regulation of cellular quiescence, a state in which cells have exited the cell cycle but remain capable of re- entering it, in early gonadogenesis. Quiescence is a fundamental cellular property that allows stem cells to persist over time without losing developmental potential. In the third aim, we will study how temporal and environmental information controls the entry into and emergence from quiescence of gonadal blast cells. Environmental regulation of developmental progression utilizes a highly conserved insulin signaling pathway, so studying how the environment impacts early gonadogenesis is potentially relevant to prevalent human diseases including diabetes and obesity. In sum, the proposed work has many implications for basic human developmental biology and for human health and disease. The deeper understanding of developmental mechanism we will achieve through these studies will be potentially applicable for developing diagnostic and therapeutic tools for human disease, a central mission of the NIH.