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Hypoxic Injury and Tumor Formation in the C. elegans Germline

线虫种系的缺氧损伤和肿瘤形成

基本信息

批准号：
9920166
负责人：
Marc R Van Gilst
金额：
$ 35.3万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920166
关键词：
Ablation Affect Animal Model Animals Biological Biological Process Blood Circulation Caenorhabditis elegans Cause of Death Cell Death Cell Hypoxia Cell division Cell physiology Cells Chemicals Collection Country Cues Development Environment Event Failure Genes Genetic Genetic Screening Goals Growth Health Human Hypoxia Impairment Injury Intervention Invertebrates Investigation Malignant Neoplasms Measures Metabolic Mitochondria Mitochondrial Proteins Modeling Modernization Mutagenesis Myocardial Infarction Nematoda Neoplasm Metastasis Organelles Osmoregulation Oxidative Phosphorylation Oxygen Pathologic Pathway interactions Physiological Physiology Property Proteins RNA Interference RNA interference screen Reporter Research Research Personnel Resistance Severities Signal Pathway Societies Somatic Cell Stroke Swelling Technology Testing Time Tissues Translations Variant Warburg Effect carcinogenesis cell type deprivation design disability fighting genome-wide glycogen metabolism human disease insight insulin signaling interest lipid metabolism mitochondrial dysfunction novel prevent promoter protein aggregation protein folding response tool tumor tumorigenesis

项目摘要

Project Summary/Abstract Oxygen is critical for all aspects of human physiology. Accordingly, oxygen deprivation can significantly impair or alter cellular functions, which can have devastating consequences to human health and viability. Physiological events that block circulation and prevent the delivery of oxygen, such as heart attack or stroke, cause lethal damage to affected tissues and comprise the leading cause of death and disability in Western countries. In other physiological contexts, hypoxia can stimulate the growth and metastasis of cancer, another human disease of considerable significance. For these reasons, there is substantial interest in developing strategies for alleviating the pathological consequences of hypoxia. The nematode C. elegans has proven to be a powerful model for investigating the mechanisms of hypoxic injury and for identifying potential strategies for intervention. Enlisting the genetic advantages of C. elegans enabled mutagenic and RNAi screens which together identified over 200 genes involved in hypoxic injury. This finding was enlightening because it revealed that although the primary effect of oxygen deprivation is a simple failure of oxidative phosphorylation, the ultimate repercussions of hypoxia are decided by a multitude of metabolic and cellular functions. By discovering a plethora of new mechanisms involved in hypoxic injury C. elegans has provided a significant contribution to the field. We believe C. elegans presents the most advantageous model for further investigation into these mechanisms. The C. elegans germline harbors a diverse array of cell types and physiological environments, therefore we reasoned that it might be a particularly useful context for understanding novel ways in which hypoxia may impact cellular function. Our preliminary studies have confirmed this, and established the potential of the germline to investigate three important aspects of hypoxic injury. Our first aim is designed to identify general and cell-specific mechanisms of hypoxic injury. The second aim is to characterize a novel mechanism for inducing resistance to hypoxic injury. And our third aim is to understand how hypoxia causes tumors to form in the C. elegans germline. The powerful experimental tools and interesting physiological properties of the germline offer unique advantages for achieving each of our objectives. We expect these studies to be of considerable biomedical significance, as we will establish the potential of general and cell-specific interventions, determine the potential for inducible mechanisms of hypoxia resistance, and elucidate fundamental conserved mechanisms of hypoxia induced cancer formation.

项目总结/文摘