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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.