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: 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
• 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

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寿命是必不可少的 受生理需求和环境压力源的影响。当ER蛋白折叠的稳态是 被扰动的，一种可能被称为ER应力的潜在致命状况，被点燃。为了减轻急诊应力，一组 使用ER膜相关的传感器优先于ER折叠的产生和慢性处置 错误折叠的蛋白质。当这些适应性反应不足时，UPR激活了亲细胞死亡过程 - es。由于其关键的管家角色，UPR在多细胞生物的生长中至关重要 不足会导致人类有害状况，包括糖尿病，神经退行性变性和癌症。 几十年来，UPR主要在体外研究，在单细胞模型生物和分化的细胞中 线路，可以在UPR不足或无法概括整个多细胞的复杂性的线路上生存 有机体。因此，针对IPR相关疾病的有效医疗疗法的设计 Quires全身UPR模型，可以在其中发展对影响的机械理解 增长，压力抵抗力和亲死亡决策的UPR。 我的长期研究目标是开发一个具有独特优势的进化不同的模型系统 在整个身体环境中揭示UPR，以对这一基本sig-的全面理解 体内naling途径。为了实现这一目标，我们的研究解决了UPR的基本知识差距 植物模型拟南芥，是由于植物和后生印花的保护 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UPR 身体环境。向前迈进，我们将基于激动人心的新发现，这些发现支持存在 新型信号转导途径也取决于生长和应力中保守的UPR传感器 正如新确定的在体内不可抗拒的ER应力条件下，与ER应力相关细胞死亡的效应子。 具体而言，我们将重点关注1）蛋白质磷酸化变化的作用，具体取决于最保守的 UPR传感器，蛋白激酶和核糖核酸酶IRE1在生长和ER应力缓解方面； 2）特征 - 通过全身前向遗传学发现的细胞死亡的新型非冗余效应子的酶化 屏幕和3）构成保守UPR的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应力的新的非惯性机制 回复; 2）识别与未解决的ER应力生存的功能相关性的关键细胞命运效应子 体内和3）扩大了与其他交点处的UPR信号转导的理解的前沿 在全身系统中运行的生物途径。从长远来看，我们的研究将有助于 在细胞级别上了解UPR，并显着提高我们对UPR体内的理解，从而 克服瓶颈，以制定有效的治疗剂来改善与UPR相关的人类状况。