Molecular Mechanisms of Lipid Droplet Biogenesis

脂滴生物发生的分子机制

• 批准号: 9178664
• 负责人: JAMES A OLZMANN
• 金额: $ 29.38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178664
• 关键词: Aging; Area; Biochemical; Biogenesis; Biology; Biotinylation; Cardiovascular Diseases; Cells; Cellular biology; Collaborations; Communities; Critical Pathways; Cytoplasm; Data; Development; Diabetes Mellitus; Disease; Dissection; Endoplasmic Reticulum; Epidemic; Etiology; Fatty Liver; Fatty acid glycerol esters; Fluorescence Microscopy; Functional disorder; Future; Genes; Genetic; Genomic approach; Goals; Growth; Human; Label; Libraries; Link; Lipid Mobilization; Lipids; Liver diseases; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Mediating; Membrane; Metabolic Diseases; Metabolic Pathway; Methods; Molecular; Nutrient; Obesity; Organelles; Pathogenesis; Pathway interactions; Peripheral; Phospholipids; Prevalence; Production; Proteins; Proteome; Proteomics; RNA interference screen; Recruitment Activity; Regulation; Regulatory Pathway; Research; Role; Site; Source; System; Technology; Therapeutic Intervention; Triglycerides; Ubiquitin; Ubiquitination; United States; Yeasts; base; cell type; density; experience; functional genomics; genetic regulatory protein; human disease; insight; interest; lipid metabolism; membrane biogenesis; metabolomics; monolayer; new therapeutic target; novel; novel therapeutics; protein complex; protein protein interaction; public health relevance; screening; small hairpin RNA; small molecule inhibitor; stem; time use; treatment strategy; whole genome

DESCRIPTION (provided by applicant): The prevalence of metabolic diseases has reached epidemic proportions in the United States. In cells, nutrients are stored as triacylglycerol (i.e. at) in lipid droplets (LDs), a conserved endoplasmic reticulum-derived organelle that is consists of a neutral lipid core encircled by a phospholipid monolayer decorated with regulatory proteins. Storage of triacylglycerol in LDs is not only critical for energy production and as a source of membrane precursors, but is central to the pathogenesis of metabolic diseases, such as obesity, diabetes, and cardiovascular disease, and has been linked to aging and cancer. For years LDs were thought of as inert cytoplasmic fat globules and there was little interest among the scientific research community. The recognition that LDs are integrally involved in the etiology of multiple diseases and that LDs are extremely dynamic organelles has paved the way for a burgeoning area of research with the potential to make a significant impact on future treatment strategies for metabolic diseases. LDs fundamentally function as hubs of cellular lipid metabolism, and it is essential that we understand the mechanisms that regulate LD biogenesis and function. Therefore, my proposed research will specifically: 1) Exploit advanced functional genomic strategies to generate a high-density epistatic map of all genes required for LD biogenesis in human cells, 2) Use metabolomics technologies to define the functional impact of ER-LD ubiquitination machinery in LD biogenesis and lipid metabolism, and 3) Utilize proximity labeling proteomic methods to define ER subdomains specialized for LD biogenesis and to determine the temporal dynamics of LD proteome maturation. Integration of these complementary studies will break new ground in cell biology and metabolic disease treatment strategies by advancing our understanding of the mechanisms underlying LD biogenesis and the molecular basis of LD dysfunction in human diseases.

描述（由申请人提供）：代谢性疾病的患病率在美国已经达到流行病的程度。在细胞中，营养物质以三酰基甘油（即at）的形式储存在脂滴（ld）中，脂滴是一种保守的内质网衍生的细胞器，由中性脂核组成，脂核被修饰有调节蛋白的磷脂单层包围。甘油三酯在ld中的储存不仅对能量产生和作为膜前体的来源至关重要，而且对代谢性疾病（如肥胖、糖尿病和心血管疾病）的发病机制至关重要，并且与衰老和癌症有关。多年来，ld被认为是惰性的细胞质脂肪球，在科学研究界几乎没有兴趣。认识到ld与多种疾病的病因学密切相关，并且ld是极具活力的细胞器，这为一个新兴的研究领域铺平了道路，并有可能对未来代谢性疾病的治疗策略产生重大影响。LD从根本上起着细胞脂质代谢中心的作用，我们有必要了解调节LD生物发生和功能的机制。因此，我提出的研究将具体如下：1)利用先进的功能基因组策略生成人类细胞中LD生物发生所需的所有基因的高密度上位图谱；2)利用代谢组学技术确定ER-LD泛素化机制在LD生物发生和脂质代谢中的功能影响；3)利用接近标记蛋白质组学方法确定LD生物发生专门的ER亚域，并确定LD蛋白质组成熟的时间动态。这些互补研究的整合将通过促进我们对LD生物发生机制和人类疾病LD功能障碍的分子基础的理解，在细胞生物学和代谢性疾病治疗策略方面开辟新的领域。