Coping with stress: the cellular maintenance of embryonic development

描述（由申请人提供）：环境的突然变化可能会破坏细胞过程。细胞具有损伤控制机制来科普这些环境“压力”，因此对这种外部损伤表现出一定的耐受性。但细胞也可能非常脆弱;环境压力会导致细胞缺陷，而这些缺陷是某些神经退行性疾病和衰老的基础。在胚胎发育的背景下，细胞必须执行一组程序化的快速细胞分裂，这在很大程度上取决于细胞骨架蛋白的作用，其结构和功能对环境应激高度敏感。胚胎如何在环境压力下保持细胞功能和正常发育？ 本研究计划的目标是确定果蝇胚胎体内环境应激耐受性的分子和细胞机制。培训将采取创新的方法，强调使用显微镜和发育遗传学技术来定义和操纵胚胎耐热性。胚胎热应激表型将在细胞分辨率下进行剖析（1）在多个基因型中，（2）在具有稳定细胞骨架的候选蛋白质的表达被破坏的胚胎中，以及（3）在来自不同热环境的野生果蝇的天然分离株中。这项研究将产生广泛的影响，有助于我们对细胞如何应对环境压力的基本知识，并确定在细胞和整个生物体水平上作为压力耐受基础的候选途径。 公共卫生相关性：细胞应对环境压力的能力对健康至关重要。影响人类细胞的一种类型的环境应激是氧化应激，其由有氧呼吸期间的活性氧物质的产生或作为热应激的副产物而产生。氧化应激已被证明会导致人类神经退行性疾病，如帕金森氏症和阿尔茨海默氏症，以及衰老的一般现象。然而，我们不知道氧化应激如何影响细胞生理学，从而导致这些疾病的病理基础。这项研究将有助于我们基本了解细胞如何经历环境压力，哪些细胞成分受影响最大，以及细胞如何在压力下保持健康功能。我们的研究结果将提供候选途径，可以对未来的治疗发展进行研究。

DESCRIPTION (provided by applicant): Sudden changes in the environment can disrupt cellular processes. Cells possess damage-control mechanisms to cope with these environmental "stresses", and thus exhibit some tolerance to such external insults. But cells can also be quite vulnerable; environmental stress causes cellular defects that are the basis of certain neurodegenerative diseases and aging. In the context of embryonic development, cells must execute a programmed set of rapid cell divisions, which are largely dependent on the action of cytoskeletal proteins whose structures and functions are highly sensitive to environmental stress. How do embryos maintain cellular function and normal development in the face of environmental stress? The goal of this research program is to identify the molecular and cellular mechanisms that underlie tolerance to environmental stress in vivo in Drosophila melanogaster embryos. The training will take an innovative approach by emphasizing the use of techniques in microscopy and developmental genetics to define and manipulate embryonic thermal tolerance. The embryonic thermal stress phenotype will be dissected at cellular resolution (1) across multiple genotypes, (2) in embryos with disrupted expression of candidate proteins that stabilize the cytoskeleton, and (3) among natural isolates of wild Drosophila from distinct thermal environments. This research will have a broad impact by contributing to our basic knowledge of how cells respond to environmental stress and by identifying candidate pathways that are the basis of stress tolerance at both the cellular and whole-organism levels. PUBLIC HEALTH RELEVANCE: The ability for cells to respond to environmental stress is fundamental to health. One type of environmental stress that affects human cells is oxidative stress, which results from the production of reactive oxygen species during aerobic respiration or as a byproduct of thermal stress. Oxidative stress has been shown to cause human neurodegenerative diseases, such as Parkinson's and Alzheimer's, as well as the general phenomenon of aging. However, we do not know how oxidative stress affects cellular physiology and thereby causes the basis of these disease pathologies. The proposed research will contribute to our basic understanding of how cells experience environmental stress, what cellular components are most affected, and how cells maintain healthy function in the presence of stress. Our findings will provide candidate pathways that can be investigated toward the future development of treatments.