Unfolded protein response in the model species Arabidopsis thaliana

模式物种拟南芥中未折叠的蛋白质反应

• 批准号: 10386462
• 负责人: Federica Brandizzi
• 金额: $ 12.5万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386462
• 关键词: Address; Animal Model; Biological; Biological Models; Cell Death; Cell Death Process; Cell Differentiation process; Cell Line; Cells; Cessation of life; Chronic; Defect; Diabetes Mellitus; Disease; Effector Cell; Endoplasmic Reticulum; Eukaryota; Genetic; Genetic Screening; Genomics; Goals; Growth; Homeostasis; Housekeeping; Human; In Vitro; Knowledge; Life; Link; Malignant Neoplasms; Medical; Membrane; Modeling; Molecular; Monitor; Mouse-ear Cress; Nerve Degeneration; Organism; Pathway interactions; Phosphorylation; Physiological; Plant Model; Plants; Production; Protein Biosynthesis; Protein Kinase; Proteins; Research; Resistance; Resources; Ribonucleases; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stress; Work; biological adaptation to stress; body system; design; endoplasmic reticulum stress; environmental stressor; forward genetics; frontier; improved; in vivo; misfolded protein; novel; protein folding; response; secretory protein; sensor; targeted treatment; therapeutically effective; tool; transcription factor

Protein folding in the endoplasmic reticulum (ER) is indispensable for the life of the cell and constantly chal- lenged by physiological demands and environmental stressors. When the homeostasis of ER protein folding is perturbed, a potentially lethal condition, known as ER stress, is ignited. To mitigate ER stress, a set of con- served ER membrane-associated sensors prioritizes the production of ER foldases and disposal of chronically misfolded proteins. When these adaptive responses are insufficient, the UPR activates pro-cell death process- es. Due to its critical housekeeping roles, the UPR is essential during growth of multicellular organisms and insufficiency leads to harmful conditions in humans, including diabetes, neurodegeneration, and cancer. For decades the UPR has been studied mainly in vitro, in unicellular model organisms and in differentiated cell lines, which can survive UPR insufficiency or are unable to recapitulate the complexity of whole multicellular organisms. Because of this, the design of effective medical therapies targeting UPR-associated diseases re- quires whole-body UPR models where it is possible to develop a mechanistic understanding of the impact of the UPR in growth, stress resistance and pro-death decisions. My long-term research goal is to develop an evolutionarily distinct model system with unique advantages for uncovering the UPR in a whole-body context to formulate a comprehensive understanding of this essential sig- naling pathway in vivo. Towards this goal, our research addresses fundamental knowledge gaps of the UPR in the plant model species Arabidopsis thaliana, because of the conservation of plant and metazoan UPRs and the vast genetics and genomics resources that we have developed and leveraged to study the UPR in whole- body context. Moving forward, we will build upon our exciting new findings, which support the existence of novel signal transduction pathways depending upon the conserved UPR sensors in growth and stress, as well as newly identified effectors of ER stress-related cell death in conditions of unresolvable ER stress in vivo. Specifically, we will focus on 1) the role of protein phosphorylation changes depending on the most conserved UPR sensor, the protein kinase and ribonuclease IRE1, in growth and ER stress mitigation; 2) the characteri- zation of novel non-redundant effectors of cell death discovered through a whole-body forward genetics screen, and 3) the mechanisms which underlie the unique signal transduction pathways of the conserved UPR transcription factors. These efforts will 1) define new non-conventional mechanisms that modulate ER stress response; 2) identify critical cell fate effectors with a functional relevance for unresolved ER stress survival in vivo, and 3) expand the frontiers of the understanding of UPR signal transduction at the intersection with other biological pathways operating in a whole-body system. In the long term, our research will contribute to the knowledge of the UPR at the cellular level and significantly advance our understanding of the UPR in vivo, thus overcoming bottlenecks in formulating effective therapeutics to ameliorate human conditions linked to the UPR.

内质网（ER）中的蛋白质折叠对于细胞的生命是必不可少的，并且不断地改变。 受生理需求和环境压力的影响。当内质网蛋白折叠的稳态被破坏时， 受到干扰，一种潜在的致命条件，称为ER应激，被点燃。为了缓解ER压力，一系列的con. 服务的ER膜相关传感器优先考虑ER折叠酶的生产和长期处理 错误折叠的蛋白质当这些适应性反应不足时，UPR激活促细胞死亡过程- es.由于其关键的管家作用，UPR在多细胞生物的生长过程中是必不可少的， 营养不足会导致人类的有害状况，包括糖尿病、神经变性和癌症。 几十年来，UPR的研究主要集中在体外、单细胞模型生物和分化细胞中 线，这可以生存UPR不足或无法概括整个多细胞的复杂性， 有机体正因为如此，针对UPR相关疾病的有效药物治疗的设计重新成为可能。 需要全身普遍定期审议模型，其中有可能对 普遍定期审议在增长、抗压力和支持死亡的决定方面的作用。 我的长期研究目标是开发一个具有独特优势的进化独特的模型系统， 在整体背景下揭示普遍定期审议，以全面理解这一重要标志， naling途径在体内。为了实现这一目标，我们的研究解决了普遍定期审议的基本知识差距， 植物模式物种拟南芥，由于植物和后生动物UPR的保护， 我们已经开发和利用了大量的遗传学和基因组学资源来研究整个普遍定期审议- 身体环境展望未来，我们将建立在我们令人兴奋的新发现的基础上，这些发现支持了 新的信号转导途径依赖于保守的UPR传感器在生长和胁迫，以及 作为新鉴定的在体内不可解决的ER应激条件下ER应激相关细胞死亡的效应物。 具体来说，我们将重点放在1）蛋白质磷酸化的作用变化取决于最保守的 UPR传感器，蛋白激酶和核糖核酸酶IRE 1，在生长和ER应激缓解中的作用; 2）UPR传感器的特性， 通过全身正向遗传学发现新的非冗余细胞死亡效应子 筛选; 3）保守的UPR独特的信号转导途径的机制 转录因子这些努力将1）确定新的非传统机制，调节ER应激 2）鉴定与未解决的ER应激存活具有功能相关性的关键细胞命运效应子， 3）扩大了UPR信号转导与其他信号转导交叉点的理解前沿， 在整个身体系统中运行的生物途径。从长远来看，我们的研究将有助于 在细胞水平上的UPR知识，并显着推进我们对体内UPR的理解，因此， 克服在制定有效疗法以改善与普遍定期审议相关的人类状况方面的瓶颈。