Dual transcriptional programs coordinate lipogenic and membrane stress responsive programs in C. elegans - Supplement

双转录程序协调线虫的脂肪生成和膜应激反应程序 - 补充

• 批准号: 10798828
• 负责人: Amy Karol Walker
• 金额: $ 16.75万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798828
• 关键词: Affect; Aging; Alzheimer' s Disease; Animals; Biochemical; Biochemistry; Biological Assay; Caenorhabditis elegans; Calories; Carbon; Cell physiology; Cells; Cellular Stress; Cellular biology; Complement; Data; Epigenetic Process; Esthesia; Genetic; Genetic Screening; Genetic Transcription; Golgi Apparatus; Guanosine Triphosphate Phosphohydrolases; HMGB1 gene; Homeostasis; Human; Intestines; Investigation; Lecithin; Link; Lipids; Membrane; Metabolic; Metabolic Pathway; Metabolism; Modeling; Modification; Molecular; Neurodegenerative Disorders; Nutrient; Organelles; Output; Parkinson Disease; Pathway interactions; Phospholipids; Play; Process; Production; Property; Regulation; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; SRE-1 binding protein; Signal Transduction; Source; Stress; biological adaptation to stress; experimental study; human disease; insight; lipid metabolism; metabolomics; programs; transcription factor

Metabolism can affect the aging process through many mechanisms. The effects of calorie levels and the sensation of nutrient sources are powerful regulators. Other metabolic pathways may affect aging by acting as signaling or transcriptional regulators. The 1 carbon cycle has multiple links to aging, particularly through the production of the methyl donor S-adenosylmethionine (SAM). SAM is critical for epigenetic modification, which can affect many cellular processes, including aging. SAM is also important for the production of a phospholipid, phosphatidylcholine (PC), which is a major membrane component. We propose to study how one 1CC metabolite, PC, impacts aging though it’s role in a membrane stress pathway. Using a long-lived C. elegans model (sams-1) and human cell-based assays, we found that lowering PC induces a stress response in the Golgi, limiting the GTPase ARF-1.2/ARF1, which is a critical regulator of Golgi function. One effect of this stress response is the maturation of a membrane-intrinsic transcription factor, SBP-1/SREBP-1, to restore lipid homeostasis. We also found that a compensatory program is upregulated that produces an alternative ARF, arf- 1.1. to support Golgi function. We have identified at least one transcription factor, LET-607, which is also intrinsic to the membrane, as a regulator of this process. Thus, the Golgi stress response has multiple transcriptional outputs that play specific roles in correcting organelle misfunction. Finally, Golgi stress may be important in multiple neurodegenerative diseases, suggesting our studies could have a broad impact outside the aging field. Our proposal is based on data from multiple genetic screens, metabolomic studies, and other unbiased approaches. Next, our plan is to use a combination of cell biology, genetics and biochemistry several key questions. First, we will explore the basic cell biology of the Golgi stress response, which is not well understood. Second, we will determine how the LET-607 transcription factor is regulated during the stress response. These experiments will be complemented by our investigation on the molecular and biochemical basis explaining how ARF-1.1 can function when membrane conditions limit ARF-1.2. Finally, we have found that ARF-1.2 selectively disappears from the intestine in aging C. elegans. Because regulation of yolk secretion has important connections to aging, it is important to understand what regulates this loss of ARF-1.2 and how it might impact aging in sams-1 animals. Metabolites such as SAM and PC may have distinct roles in aging and stress in a variety of contexts, as these molecules can contribute to a variety of different processes. By delineating molecular mechanisms downstream of SAM and PC that affect membrane properties, we will uncover how specific aspects of 1 carbon and lipid metabolism drive changes in aging and stress.

代谢可以通过许多机制影响衰老过程。卡路里水平的影响和 营养来源的感觉是强大的调节器。其他代谢途径可能会通过起作用 信号传导或转录调节器。 1碳循环与衰老有多个联系，尤其是通过 产生甲基供体S-腺苷硫氨酸（SAM）。 SAM对于表观遗传修饰至关重要， 可能影响许多细胞过程，包括衰老。山姆对于生产 磷脂，磷脂酰胆碱（PC），这是主要的膜成分。我们建议研究一个 1CC代谢产物PC会影响衰老，尽管它在膜应力途径中的作用。使用长期寿命C。 秀丽隐杆线模型（SAMS-1）和基于人类细胞的测定法，我们发现降低PC会影响压力反应 高尔基体限制了GTPase ARF-1.2/ARF1，这是高尔基函数的关键调节剂。一个效果 压力反应是膜 - 内膜转录因子SBP-1/SREBP-1的成熟，以恢复脂质 稳态。我们还发现，更新了一个补偿计划，该计划产生了替代的ARF，ARF- 1.1。支持高尔基函数。我们已经确定了至少一个转录因子let-607，这也是 膜的固有，作为此过程的调节剂。那，高尔基应力反应有多个 转录输出在纠正细胞器函数误差中起特定角色。最后，高尔基压力可能是 在多种神经退行性疾病中很重要，这表明我们的研究可能会产生广泛的影响 衰老场。 我们的建议基于来自多个遗传筛查，代谢组学研究和其他公正的数据 方法。接下来，我们的计划是结合细胞生物学，遗传学和生物化学几个关键 问题。首先，我们将探索高尔基应力反应的基本细胞生物学，这不是很好 理解。其次，我们将确定在应力期间如何调节Let-607转录因子 回复。这些实验将通过我们对分子和生化基础的研究来完成 解释当膜条件限制ARF-1.2时，ARF-1.1如何起作用。最后，我们发现 ARF-1.2在衰老的秀丽隐杆线虫中有选择地从肠子中消失。因为蛋黄分泌的调节有 与衰老的重要联系，重要的是要了解是什么调节了ARF-1.2的损失及其如何 可能会影响SAMS-1动物的衰老。 SAM和PC等代谢物可能在衰老和 在各种情况下的压力，因为这些分子可以促进各种不同的过程。经过 划定影响膜特性的SAM和PC下游的分子机制，我们将 发现1个碳和脂质代谢的特定方面如何驱动衰老和压力的变化。