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Bipartite regulation of cellular osmosensing in C. elegans

线虫细胞渗透感应的双向调节

基本信息

批准号：
9184570
负责人：
SAMUEL T LAMITINA
金额：
$ 29.26万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9184570
关键词：
Address Aging Aging-Related Process Animal Model Animals Bacteria Biological Assay Biology Buffers Caenorhabditis elegans Cell Culture Techniques Cell Volumes Cell physiology Cells Chronic Kidney Failure Complex Crowding Cultured Cells Cytoskeleton Data Defect Detection Diabetic Neuropathies Diagnosis Disease Early Diagnosis Early Intervention Environment Exhibits Extracellular Matrix Extracellular Protein Failure Gene Expression Genes Genetic Homeostasis Human Hypertension Immune response Integral Membrane Protein Kidney Kidney Diseases Kidney Failure Knowledge Lead Life Mammalian Cell Mechanics Mediating Membrane Modeling Molecular Mucins Names Osmoregulation Pathway interactions Peripheral Nervous System Diseases Physiological Physiological Processes Physiology Play Process Property Proteins Quality Control Regulation Role Signal Pathway Signal Transduction Stress Stress-Induced Protein Stretching Structure Subcutaneous Tissue System Testing Tissues Water Yeasts age related base biological adaptation to stress blood pressure regulation cell growth regulation genetic approach genome-wide analysis heat shock transcription factor immune activation in vivo insight mechanotransduction misfolded protein mutant novel therapeutic intervention novel therapeutics polyglutamine programs protein aggregation protein misfolding proteostasis public health relevance response reverse genetics sensor solute stressor urinary

项目摘要

DESCRIPTION (provided by applicant): The physiological process of maintaining cellular solute and water content is termed osmotic homeostasis, or osmoregulation, and is essential for all forms of cellular life. In humans, osmotic homeostasis plays vital roles in several contexts, including regulation of the kidney's urinary concentrating mechanism, control of blood pressure, and activation of immune responses. Osmotic dyshomeostasis is associated with several age- related diseases, including chronic kidney disease, renal failure, hypertension, and peripheral neuropathy. Despite the obvious importance of osmoregulation in both physiological and pathophysiological disease states, little is known about the mechanisms by which animal cells sense and respond to osmotic stress. A better understanding of these mechanisms may allow earlier detection and intervention in age-related diseases. Most studies of osmoregulation have been carried out using cultured cells, which fail to mimic the complex environments in which most cells are found. These studies have led to many hypotheses to explain the mechanism(s) of cellular osmosensing, such as mechanical 'stretching' of the membrane and/or cytoskeleton, macromolecular crowding, and alterations in cytoplasmic ionic content, to name a few. However, there is little data supporting any of these models. To gain an in vivo perspective on mechanisms of cellular osmosensing in animals, we are studying this process in the model organism C. elegans, in which complex cell-cell and cell- extracellular matrix (ECM) interactions are preserved. Using unbiased forward and reverse genetic approaches, we discovered critical roles for the extracellular matrix (Rohlfing et al, PLoS Genetics, 2011) and protein misfolding (Moronetti Mazzeo et al, PNAS, 2012) in the regulation of cellular osmosensing in C. elegans. Based on these findings we hypothesize that animal cells use both mechanotransduction and protein damage detection mechanisms to sense osmotic disturbances and activate osmosensitive gene expression. In Aim 1, we will determine if the C. elegans cuticular ECM acts as a structural 'osmosensor' to transduce information via interactions between the mucin-like protein OSM-8 and a transmembrane protein PTR-23. In Aim 2, we will define the native proteins susceptible to stress-induced protein aggregation and determine how aging and aging regulators influence osmotic stress induced protein damage and osmosensitive gene expression. In Aim 3, we will examine how ECM and protein damage detection pathways interact with each other to control osmoregulatory physiology. Our studies take maximal advantage of the C. elegans system to fill an important gap in our knowledge of metazoan cell physiology. These findings will provide transformative insights into the conserved process of osmoregulation that will allow us to better understand, detect, and manage age-related diseases of osmotic dyshomeostasis.

描述（由申请人提供）：维持细胞溶质和水含量的生理过程称为渗透稳态或渗透调节，对于所有形式的细胞生命都是必不可少的。在人类中，渗透压稳态在多种情况下发挥着至关重要的作用，包括调节肾脏的尿液浓缩机制、控制血压和激活免疫反应。渗透压失调与多种年龄相关疾病有关，包括慢性肾病、肾衰竭、高血压和周围神经病。尽管渗透调节在生理和病理生理疾病状态中具有明显的重要性，但人们对动物细胞感知和响应渗透应激的机制知之甚少。更好地了解这些机制可能有助于更早地发现和干预与年龄相关的疾病。大多数渗透调节研究都是使用培养细胞进行的，这些细胞无法模拟大多数细胞所处的复杂环境。这些研究提出了许多假设来解释细胞渗透传感的机制，例如膜和/或细胞骨架的机械“拉伸”、大分子拥挤以及细胞质离子含量的改变等等。然而，支持这些模型的数据很少。为了获得动物细胞渗透感应机制的体内视角，我们正在模型生物秀丽隐杆线虫中研究这一过程，其中保留了复杂的细胞-细胞和细胞-细胞外基质（ECM）相互作用。使用无偏正向和反向遗传方法，我们发现细胞外基质（Rohlfing 等人，PLoS Genetics，2011）和蛋白质错误折叠（Moronetti Mazzeo 等人，PNAS，2012）在秀丽隐杆线虫细胞渗透感应调节中的关键作用。基于这些发现，我们假设动物细胞使用机械转导和蛋白质损伤检测机制来感知渗透压紊乱并激活渗透敏感基因表达。在目标 1 中，我们将确定线虫表皮 ECM 是否充当结构性“渗透传感器”，通过粘蛋白样蛋白 OSM-8 和跨膜蛋白 PTR-23 之间的相互作用来转换信息。在目标 2 中，我们将定义易受应激诱导的蛋白质聚集影响的天然蛋白质，并确定衰老和衰老调节剂如何影响渗透应激诱导的蛋白质损伤和渗透敏感基因表达。在目标 3 中，我们将研究 ECM 和蛋白质损伤检测途径如何相互作用以控制渗透调节生理学。我们的研究最大限度地利用了秀丽隐杆线虫系统，以填补我们在后生动物细胞生理学知识方面的一个重要空白。这些发现将为渗透调节的保守过程提供变革性的见解，使我们能够更好地理解、检测和管理与年龄相关的渗透失调疾病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans.

DOI：
10.1371/journal.pgen.1007038
发表时间：
2017-10
期刊：
PLoS genetics
影响因子：
4.5
作者：
Das R;Melo JA;Thondamal M;Morton EA;Cornwell AB;Crick B;Kim JH;Swartz EW;Lamitina T;Douglas PM;Samuelson AV
通讯作者：
Samuelson AV

Models and mechanisms of repeat expansion disorders: a worm's eye view.

重复扩张障碍的模型和机制：蠕虫的视角。