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

双转录程序协调线虫的脂肪生成和膜应激反应程序

• 批准号: 10571854
• 负责人: Amy Karol Walker
• 金额: $ 43.05万
• 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/10571854
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Binding; Biochemical; Biochemistry; Biological Assay; Caenorhabditis elegans; Calories; Carbon; Cell Aging; Cell Line; Cell physiology; Cells; Cellular Stress; Cellular biology; Compensation; Complement; Data; Egg Yolk Proteins; Endoplasmic Reticulum; Environment; Enzymes; Epigenetic Process; Esthesia; Genetic; Genetic Screening; Genetic Transcription; Golgi Apparatus; Guanosine Triphosphate Phosphohydrolases; HMGB1 gene; Health; Homeostasis; Human; In Vitro; Individual; Intestines; Investigation; Lecithin; Link; Lipid Bilayers; Lipids; Lipodystrophy; Longevity; Mammalian Cell; Measures; Membrane; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Modification; Molecular; Mutation; N-terminal; Nature; Neurodegenerative Disorders; Nutrient; Nutritional; Organelles; Orthologous Gene; Output; Parkinson Disease; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Phospholipids; Play; Process; Production; Property; Proteins; Regulation; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; SRE-1 binding protein; Signal Transduction; Site; Source; Stress; Tissues; arm; biological adaptation to stress; experimental study; human disease; in vivo; insight; lipid metabolism; metabolic phenotype; metabolomics; mutant; paralogous gene; programs; repaired; response; 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.

新陈代谢可以通过多种机制影响衰老过程。卡路里水平和 对营养源的感觉是强有力的调节器。其他代谢途径可能通过发挥以下作用来影响衰老 信号或转录调节因子。1碳循环与衰老有多种联系，特别是通过 甲基供体S-腺苷蛋氨酸的生产。山姆对表观遗传修饰至关重要， 这会影响许多细胞过程，包括衰老。萨姆对制作一部 磷脂，磷脂酰胆碱(PC)，它是膜的主要成分。我们建议研究如何 1CC代谢物PC通过其在膜应激途径中的作用影响衰老。使用长寿的C. Elgans模型(SAMS-1)和基于人类细胞的分析，我们发现降低PC诱导了应激反应 高尔基体，限制了GTP酶ARF-1.2/ARF1，它是高尔基体功能的关键调节因子。这样做的一个效果是 应激反应是一种膜内源性转录因子SBP-1/SREBP-1的成熟，以恢复脂质 动态平衡。我们还发现，一个补偿计划被上调，从而产生一个替代的ARF，ARF- 1.1.以支持高尔基体功能。我们已经鉴定了至少一个转录因子let-607，它也是 膜上固有的，作为这一过程的调节器。因此，高尔基体应激反应有多个 在纠正细胞器功能障碍方面发挥特定作用的转录输出。最后，高尔基人的压力可能是 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在 老化字段。 我们的建议是基于来自多个基因筛查、新陈代谢研究和其他公正的数据 接近了。接下来，我们的计划是结合细胞生物学、遗传学和生物化学的几个关键 问题。首先，我们将探索高尔基体应激反应的基本细胞生物学，这是不好的 明白了。其次，我们将确定let-607转录因子在应激过程中是如何调节的 回应。这些实验将得到我们对分子和生化基础的研究的补充 解释当膜条件限制ARF-1.2时，ARF-1.1如何发挥作用。最后，我们发现， ARF-1.2在老化的线虫体内选择性地从肠道中消失。因为对蛋黄分泌的调节 对于衰老的重要联系，重要的是要了解是什么调节了ARF-1.2的这种丢失，以及它是如何 可能会影响SAMS-1动物的衰老。代谢物如SAM和PC可能在衰老和 应激在不同的环境中，因为这些分子可以促进各种不同的过程。通过 描述影响膜性能的SAM和PC下游的分子机制，我们将 揭示碳水化合物和脂肪代谢的特定方面如何驱动衰老和压力的变化。