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

线虫早期性腺发生的空间、时间和环境调节

基本信息

批准号：
9321881
负责人：
Iva S Greenwald
金额：
$ 32.88万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321881
关键词：
Ablation Alpha Cell Animal Model Beta Cell Biological Assay Biology Birth Order Blast Cell Caenorhabditis elegans Cancer Biology Cell Communication Cell Cycle Cell Cycle Progression Cell Differentiation process Cells Competence Daughter Development Developmental Biology Diabetes Mellitus Diagnostic Diapause Disease Environment Event Fluorescence Gene Targeting Genes Genetic Genetic Screening Genetic Transcription Genome engineering Goals Gonadal structure Grant Health Homeostasis Human Human Development Image Immune System Diseases Insulin Signaling Pathway Lateral Learning Lobular Neoplasia Maintenance Malignant Neoplasms Measures Mediating Methods Microscope Microscopy Mission Molecular Monitor Mosaicism Nuclear Obesity Organogenesis Orthologous Gene PTEN gene Parents Pathway interactions Pattern Phase Primordium Process Property Regulation Reporter Role Signal Transduction Sister Spottings Stem cells Stochastic Processes Study models Sum System TCF3 gene Testing Therapeutic Time Tissues United States National Institutes of Health Uterus WNT Signaling Pathway Work base cancer stem cell cell fate specification cell growth regulation developmental disease genetic analysis human disease in vivo insulin signaling intercellular communication life history nervous system disorder neuronal cell body notch protein precursor cell public health relevance tool transcription factor transcriptome

项目摘要

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.

描述（由申请人提供）：线虫是研究与人类发育和疾病普遍相关的发育生物学基本问题的首要模型生物。这项资助的总体目标是研究早期性腺发生的空间、时间和环境调节。线虫的体细胞性腺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。实现三个具体目标。其中两个目标涉及早期性腺发生中 Notch 介导的细胞间相互作用的空间模式，我们将研究随机过程如何在发育等效细胞之间产生差异，并通过 LIN-12/Notch 信号传导来解决。 Notch信号传导需求的不对称性是如何产生并促进细胞命运多样化的，这些目标的基本生物学与理解干细胞的细胞动力学、有机体发育和组织稳态的维持高度相关。体内；细胞命运重编程及其潜在的体外治疗应用；我们对Notch信号传导和使细胞命运多样化的机制的了解将直接适用于正常发育中的其他情况，因为异常的Notch活性与许多不同的情况有关。在癌症以及发育、免疫和疾病方面，拟议的工作对人类健康和疾病具有许多神经学意义。我们还将研究在不同的环境条件下如何控制性腺发生过程中细胞和形态发生事件的时间进展。细胞静止的调节，细胞已退出细胞周期但仍保持的状态在性腺发生早期，静止是一种基本的细胞特性，它允许干细胞在不失去发育潜力的情况下持续存在。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退出。发育进程的环境调节利用了高度保守的胰岛素信号通路，因此研究环境如何影响早期性腺发生可能与包括糖尿病和肥胖症在内的流行人类疾病有关。人类发育生物学和通过这些研究，我们将更深入地了解发育机制，这将有可能适用于开发人类疾病的诊断和治疗工具，这是美国国立卫生研究院的核心使命。