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

基本信息

批准号：
10615063
负责人：
Federica Brandizzi
金额：
$ 39.13万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10615063
关键词：
Address 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 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 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 genetic resource genome resource improved in vivo misfolded protein model organism novel protein folding response secretory protein sensor targeted treatment therapeutically effective tool transcription factor

项目摘要

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不可或缺的，并且不断变化。生理需求和环境压力造成的。当 ER 蛋白折叠的稳态处于如果受到干扰，就会引发一种潜在的致命状况，即内质网应激。为了减轻 ER 压力，需要采取一系列措施与 ER 膜相关的传感器优先考虑 ER 折叠酶的产生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 就会激活促细胞死亡过程 - es.由于其重要的管家作用，UPR 在多细胞生物的生长过程中至关重要，并且不足会导致人类出现有害状况，包括糖尿病、神经退行性疾病和癌症。几十年来，UPR 主要在体外、单细胞模型生物和分化细胞中进行研究细胞系，可以在 UPR 不足的情况下生存，或者无法重现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需要重新设计。需要全身 UPR 模型，以便能够对以下因素的影响产生机械性的理解：成长、抗压和支持死亡决策中的普遍定期审议。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全身范围内揭示普遍定期审议，以形成对这一基本标志的全面理解体内纳灵途径。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，我们开发并利用了大量的遗传学和基因组学资源来全面研究 UPR—— 身体背景。展望未来，我们将基于我们令人兴奋的新发现，这些发现支持了新的信号转导途径也依赖于生长和应激中保守的 UPR 传感器作为新发现的内质网应激相关细胞死亡效应物，在体内无法解决的内质网应激条件下。具体来说，我们将重点关注 1) 蛋白质磷酸化作用的变化取决于最保守的磷酸化 UPR 传感器、蛋白激酶和核糖核酸酶 IRE1，在生长和缓解 ER 应激中发挥作用； 2）特点通过全身正向遗传学发现的新型非冗余细胞死亡效应子的化筛选，以及 3) 保守 UPR 独特信号转导途径的机制转录因子。这些努力将 1) 定义调节 ER 应激的新的非常规机制回复; 2) 识别与未解决的 ER 应激生存具有功能相关性的关键细胞命运效应器 vivo，以及3）扩展了对UPR信号转导与其他信号转导交叉点的理解前沿在全身系统中运作的生物途径。从长远来看，我们的研究将有助于在细胞水平上了解 UPR 并显着促进我们对体内 UPR 的理解，从而克服制定有效疗法以改善与普遍定期审议相关的人类状况的瓶颈。