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: 10376264
• 负责人: Amy Karol Walker
• 金额: $ 22.79万
• 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/10376264
• 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; Complement; Data; Egg Yolk Proteins; Endoplasmic Reticulum; Environment; Enzymes; Epigenetic Process; Esthesia; Financial compensation; Genetic; Genetic Screening; Genetic Transcription; Golgi Apparatus; Guanosine Triphosphate Phosphohydrolases; HMGB1 Protein; Health; Homeostasis; Human; In Vitro; Individual; Intestines; Investigation; Lecithin; Light; 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-Adenosylmethionine; SRE-1 binding protein; Signal Transduction; Site; Source; Stress; Tissues; arm; base; 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.

新陈代谢可以通过许多机制影响衰老过程。卡路里水平和 营养源的感觉是强大的调节器。其他代谢途径可能会影响衰老， 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-腺苷甲硫氨酸（SAM）的产生。SAM对于表观遗传修饰至关重要， 这会影响很多细胞过程包括衰老SAM对于生产 磷脂，磷脂酰胆碱（PC），这是一个主要的膜成分。我们建议研究一个 1CC代谢产物PC通过膜应激途径影响衰老。使用长寿命的C。 在线虫模型（sams-1）和基于人类细胞的测定中，我们发现降低PC诱导了应激反应， 高尔基体，限制了GTdR ARF-1.2/ARF 1，这是高尔基体功能的关键调节因子。其中一个影响是 应激反应是膜内转录因子SBP-1/SREBP-1的成熟， 体内平衡我们还发现，一种代偿性程序被上调，产生另一种ARF， 1.1.支持高尔基体的功能。我们已经鉴定了至少一种转录因子LET-607，它也是 作为这一过程的调节剂。因此，高尔基体应激反应具有多重性， 在纠正细胞器功能失调中发挥特定作用的转录产物。最后，高尔基体压力可能是 这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， 老化场 我们的建议是基于多个基因筛选，代谢组学研究和其他无偏见的数据。 接近。下一步，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，我们将探讨高尔基体应激反应的基本细胞生物学， 明白其次，我们将确定LET-607转录因子在胁迫期间是如何调节的 反应这些实验将通过我们在分子和生物化学基础上的研究来补充 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C.优美的因为卵黄分泌的调节 重要的是要了解是什么调节ARF-1.2的这种损失，以及它是如何 可能会影响SAMS-1动物的衰老。代谢产物如SAM和PC可能在衰老中具有不同的作用， 在各种情况下，这些分子都可以产生压力，因为这些分子可以促进各种不同的过程。通过 描述SAM和PC下游影响膜特性的分子机制，我们将 揭示1碳和脂质代谢的特定方面如何驱动衰老和压力的变化。