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：
9128674
负责人：
Iva S Greenwald
金额：
$ 32.99万
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/9128674
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 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 Life Lobular Neoplasia Maintenance Malignant Neoplasms Measures Mediating Methods Microscope Microscopy Mission Monitor Nuclear Obesity Organogenesis Orthologous Gene PTEN gene Parents Pathway interactions Pattern Phase Primordium Process Property Regulation Reporter Role Signal Transduction Sister Spottings Stem Cell Development Stem cells Stochastic Processes Study models Sum System TCF3 gene Testing Therapeutic Time Tissues United States National Institutes of Health Uterus 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 molecular imaging nervous system disorder neuronal cell body notch protein precursor cell tool transcription factor transcriptome

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 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 Life Lobular Neoplasia Maintenance Malignant Neoplasms Measures Mediating Methods Microscope Microscopy Mission Monitor Nuclear Obesity Organogenesis Orthologous Gene PTEN gene Parents Pathway interactions Pattern Phase Primordium Process Property Regulation Reporter Role Signal Transduction Sister Spottings Stem Cell Development Stem cells Stochastic Processes Study models Sum System TCF3 gene Testing Therapeutic Time Tissues United States National Institutes of Health Uterus 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 molecular imaging nervous system disorder neuronal cell body notch protein precursor cell tool transcription factor transcriptome

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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（由适用提供）：秀丽隐杆线虫是一种主要的模型生物体，用于研究与人类发展和疾病一般相关性发展生物学的基本问题。该赠款的总体目标是研究秀丽隐杆线虫早期发生性发生性发生的空间，临时和环境调节。秀丽隐杆线虫的体细胞性腺是一种可实验性的模型，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，分子操纵和基因组工程，以实现三个特定目标。两个目的与空间模式有关，涉及早期性腺发生的Notch介导的细胞 - 细胞相互作用。我们将研究随机过程如何在lin-12/Notch信号解决的发展等效细胞之间产生差异，以及如何产生Notch信号的不对称性并有助于细胞脂肪的多样化。这些目标的基本生物学与理解干细胞的细胞动力学，有机发育以及体内组织稳态维持的基本生物学高度相关。细胞命运重编程，具有潜在的治疗应用；和癌症生物学。我们了解到的关于Notch信号传导和多样化细胞命运的机制将直接适用于正常发育中的其他情况，并且由于在许多不同的癌症以及发育，免疫和神经系统疾病中浸渍了异常缺口活动，因此拟议的工作对人类健康和疾病具有许多影响。我们还将研究在不同环境条件下控制性腺发生过程中细胞和形态发生事件的暂时进展。特别是，我们将研究细胞静止的调节，在这种状态下，细胞退出了细胞周期，但仍保持能够在早期性腺发生中重新进入它。静止是一种基本的细胞特性，可使干细胞随着时间的流逝而持续而不会失去发育潜力。在第三个目标中，我们将研究暂时和环境信息如何控制性腺爆炸细胞静止的进入和出现。发育进度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的性腺发生，可能与包括糖尿病和肥胖症在内的普遍性人类疾病有关。总而言之，拟议的工作对基本人类发育生物学以及人类健康和疾病具有许多影响。我们将通过这些研究实现的对发展机制的更深入了解将有可能用于开发人类疾病的诊断和治疗工具，这是NIH的核心任务。