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The Coordination of Lipid Synthesis and Breakdown in Metabolism and Aging

代谢和衰老中脂质合成和分解的协调

基本信息

批准号：
9173620
负责人：
Arjumand Ghazi
金额：
$ 30.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173620
关键词：
Address Adult Age Aging Animals Biochemical Biological Assay Caenorhabditis elegans Cardiovascular Diseases Catabolic Process Cells Characteristics Complex Coupling Data Delayed Childbearing Deposition Disease Elderly Ensure Epidemic Equilibrium Excision Fatty Acids Fatty acid glycerol esters Feedback Fertility Fluorescent in Situ Hybridization Foundations Gene Expression Genes Genetic Screening Health Homeostasis Human Hydrolysis Image Infertility Intestines Knowledge Lead Link Lipid Mobilization Lipids Lipolysis Longevity Measures Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Microscopy Modeling Molecular Genetics Mutation Nematoda Nuclear Nuclear Hormone Receptors Obesity Organism PPAR alpha Pathology Pathway interactions Physiological Population Process Production Public Health RNA Interference Regulation Reporter Genes Reproduction Research Role Signal Transduction Site Staging Testing Therapeutic Intervention Tissues Transgenic Organisms Triglycerides age related aging population base egg in vivo innovation insight lipid biosynthesis lipid metabolism mutant novel oxidation prevent reproductive research study response small molecule therapy design transcription factor transcriptome sequencing trend

项目摘要

Project Title: The coordination of lipid synthesis and degradation in metabolism and aging ABSTRACT/SUMMARY Lipid imbalances are characteristic of obesity and a feature of many age-related ailments and reproductive pathologies in humans. Yet, the relationship between lipid metabolism, aging and reproduction remains poorly studied. We propose to use the nematode C. elegans to characterize this relationship. In particular, we propose to investigate how the balance between lipid synthesis and breakdown influences an organism's rate of aging and health. In C. elegans, eliminating the germline extends lifespan. Besides fertility loss, germline removal is a major challenge to lipid metabolism because the animal needs to stop fat deposition into eggs and reorganize its lipid profile. Thus, germline-less worms provide a unique platform to understand how lipid balance is established in the cells and tissues of complex multicellular animals that are facing major physiological changes. We have discovered that fat production and degradation appear to be increased simultaneously in response to germline loss in worms. We recently demonstrated that in germline-less adults a conserved transcription factor, NHR-49, upregulate fatty-acid β-oxidation and desaturation- processes that contribute to lipid breakdown and build-up, respectively. Independently, we have also discovered that these two, and many other processes involved in lipid synthesis and degradation, are elevated in response to germline removal by the conserved transcription factors, DAF-16 and TCER-1. These data have led us to hypothesize that the coordinated enhancement of lipid synthesis and breakdown facilitates the adaptation to germline loss by ensuring lipid homeostasis. We propose to test this hypothesis by using molecular genetics, microscopy and biochemical approaches. The knowledge obtained from these studies is likely to reveal fundamental insights into the relationship of lipid metabolism, reproduction and aging. These studies are of relevance to human health and disease because they address major public health issues such as aging and obesity. The discoveries made through these experiments can lead to the discovery of therapeutic interventions targeting age-related ailments and metabolic diseases.

项目名称：代谢和衰老中脂质合成和降解的协调摘要/总结脂质失衡是肥胖的特征，也是许多与年龄相关的疾病的特征，人类生殖病理。然而，脂质代谢、衰老和生殖之间的关系仍然缺乏研究。我们建议使用线虫秀丽隐杆线虫来表征这种关系。在特别是，我们建议研究脂质合成和分解之间的平衡如何影响机体衰老和健康的速度。在秀丽隐杆线虫中，消除种系可以延长寿命。除了生育能力丧失之外，种系去除也是一个对脂质代谢的重大挑战，因为动物需要停止脂肪沉积到卵中并进行重组它的脂质分布。因此，无种系线虫提供了一个独特的平台来了解脂质平衡是如何发生的。建立在面临重大生理问题的复杂多细胞动物的细胞和组织中变化。我们发现脂肪的产生和降解似乎同时增加对蠕虫种系损失的反应。我们最近证明，在无种系的成年人中，有一个保守的转录因子 NHR-49 上调脂肪酸 β-氧化和去饱和过程，从而有助于分别是脂质分解和积聚。独立地，我们还发现这两个以及许多涉及脂质合成和降解的其他过程，由于种系去除而升高保守转录因子 DAF-16 和 TCER-1。这些数据使我们推测脂质合成和分解的协调增强促进了对种系损失的适应确保脂质稳态。我们建议通过使用分子遗传学、显微镜和生化方法。从这些研究中获得的知识可能会揭示基本的见解脂代谢、生殖和衰老的关系。这些研究与人类健康和疾病相关，因为它们涉及重大公共卫生问题老龄化、肥胖等问题。通过这些实验获得的发现可以导致发现针对与年龄相关的疾病和代谢疾病的治疗干预措施。