Deconvolution of adaptive metabolic responses of the endoplasmic reticulum

内质网适应性代谢反应的反卷积

• 批准号: 8047403
• 负责人: GOKHAN S HOTAMISLIGIL
• 金额: $ 236.34万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047403
• 关键词: Address; Adipose tissue; Adverse effects; Animals; Area; Biological; Biology; Cardiovascular Diseases; Chronic; Chronic Disease; Communicable Diseases; Complex; Degenerative Disorder; Development; Diabetes Mellitus; Discrimination; Disease; Disease Clusterings; Disease model; Endoplasmic Reticulum; Failure; Fatty Acids; Functional disorder; Future; Genomics; Goals; Homeostasis; Human; Incidence; Inflammatory Response; Insulin Resistance; Lead; Life; Lipids; Liver; Malignant Neoplasms; Medical; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Methodology; Mitochondria; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organelles; Outcome; Output; Pathology; Polyribosomes; Preparation; Prevention; Preventive; Protein Biosynthesis; Proteins; Proteome; Proteomics; RNA analysis; Reagent; Regulation; Reporting; Research; Site; Stress; Structure of beta Cell of islet; System; Technology; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Transcript; abstracting; age related; base; comparative; design; disorder control; functional status; genome-wide; global health; high throughput technology; in vivo; insight; novel; novel strategies; research study; resource guides; response; Address; Adipose tissue; Adverse effects; Animals; Area; Biological; Biology; Cardiovascular Diseases; Chronic; Chronic Disease; Communicable Diseases; Complex; Degenerative Disorder; Development; Diabetes Mellitus; Discrimination; Disease; Disease Clusterings; Disease model; Endoplasmic Reticulum; Failure; Fatty Acids; Functional disorder; Future; Genomics; Goals; Homeostasis; Human; Incidence; Inflammatory Response; Insulin Resistance; Lead; Life; Lipids; Liver; Malignant Neoplasms; Medical; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Methodology; Mitochondria; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organelles; Outcome; Output; Pathology; Polyribosomes; Preparation; Prevention; Preventive; Protein Biosynthesis; Proteins; Proteome; Proteomics; RNA analysis; Reagent; Regulation; Reporting; Research; Site; Stress; Structure of beta Cell of islet; System; Technology; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Transcript; abstracting; age related; base; comparative; design; disorder control; functional status; genome-wide; global health; high throughput technology; in vivo; insight; novel; novel strategies; research study; resource guides; response

DESCRIPTION (provided by applicant): The research area addressed in this proposal involves systems approaches to explore the mechanisms giving rise to chronic metabolic diseases such as obesity, diabetes, and cardiovascular disease with implications to cancer and other degenerative diseases. This disease cluster currently constitutes the most devastating global health problem and projected to continue to grow at tremendous rates in the next 25 years. Hence, our proposal is highly relevant to the "focus on global health". In addition, our approach to systematically decode organelle-specific protein and lipid landscape in chronic metabolic disease also relates to research theme "applying genomics and other high throughput technologies" and the outcomes of the project will be a strong guide and resource for exploiting organelle therapy as a novel platform to screen and develop therapeutics which is consistent with the translational goals of the initiative. Our research is inspired by recently emerging evidence strongly supporting that these chronic non-communicable diseases, as well as many age-related metabolic and degenerative disorders, all feature dysfunction of cellular organelles, particularly mitochondria and endoplasmic reticulum. However, there is currently little to no understanding of how these pathological conditions relate to organelle dysfunction and how chronic failure of these organelles lead to development of these pathologies. These major gaps in understanding chronic organelle adaptation, or lack thereof, limit the exploitation of novel avenues and possibilities for prevention and treatment for debilitating chronic diseases. In this project, we propose to focus on endoplasmic reticulum and systematically study this organelle and its functional output using an integrated platform of organelle-specific proteomics, lipidomics, ER-associated polysome analysis and profiling to identify all of the translational outputs of the polysomes that are subject to regulation, as well as functional perturbations in the context of metabolic disease. Our approach does not assume any prior biases regarding the homeostasis of this organelle and aims to address the mechanisms leading to its failure in a comprehensive manner not just limited to the accepted functions of this organelle in protein synthesis, folding, and, metabolism. We believe this new emerging area offers tremendous opportunities for translational possibilities and warrants a systematic approach to define the mechanistic bottlenecks in the ability of this organelle to adapt to the demands of chronic diseases. The technologies, approaches, and the models emerging from this platform will generate important insights into the biology of ER and will have applications for a broad array of chronic complex diseases. PUBLIC HEALTH RELEVANCE: Chronic metabolic diseases, such as obesity, insulin resistance, type 2 diabetes, and cardiovascular disease are among the most common diseases with adverse effects on global health. Despite their enormous burden on human life, the preventive and therapeutic opportunities are limited and there is ongoing need for new and more effective remedies. Our project aims to identify core mechanisms that give rise to these pathologies by focusing on the emerging and exciting concept of organelle dysfunction in metabolic diseases. In this proposal we will study the causes of organelle failure focusing on endoplasmic reticulum and using systematic high-throughput approaches to identify all regulated lipids and proteins in purified organelles from control and disease-afflicted tissues. The mechanism uncovered through these experiments will be instrumental in the design and implementation of preventive and therapeutic strategies and allow the general field reagents and technologies to explore the biological effects and mechanisms of nutrient exposures. The proposed studies are in excellent match with the several themes of the initiative.

描述（由申请人提供）：该提案中解决的研究领域涉及探索机制的系统方法，从而引起慢性代谢疾病，例如肥胖，糖尿病和心血管疾病，对癌症和其他退行性疾病产生影响。该疾病簇目前构成了最具破坏性的全球健康问题，预计将在未来25年内继续以巨大的速度增长。因此，我们的提议与“关注全球健康”高度相关。此外，我们在慢性代谢疾病中系统地解码细胞器特异性蛋白和脂质景观的方法还与研究主题“应用基因组学和其他高吞吐量技术”有关，该项目的结果将是一个有力的指南和资源，用于利用有机体治疗，以筛选和开发具有翻译成果的新型平台，以筛选和开发具有既定的目标的新型平台。我们的研究灵感来自最近新兴的证据，强烈支持这些慢性非传染性疾病以及许多与年龄相关的代谢和退化性疾病，所有这些疾病均具有细胞细胞器的功能障碍，尤其是线粒体和内质网。但是，目前几乎没有了解这些病理状况与细胞器功能障碍以及这些细胞器的慢性衰竭如何导致这些病理发展的发展。这些在理解慢性细胞器适应或缺乏慢性细胞器中的主要差距限制了对新型途径的剥削以及预防和治疗使人衰弱的慢性疾病的可能性。 In this project, we propose to focus on endoplasmic reticulum and systematically study this organelle and its functional output using an integrated platform of organelle-specific proteomics, lipidomics, ER-associated polysome analysis and profiling to identify all of the translational outputs of the polysomes that are subject to regulation, as well as functional perturbations in the context of metabolic disease.我们的方法没有对该细胞器的体内平衡的任何先前的偏见，旨在以全面的方式解决导致其失败的机制，不仅限于该细胞器在蛋白质合成，折叠和代谢中的可接受功能。我们认为，这个新的新兴领域为翻译可能性提供了巨大的机会，并保证一种系统的方法来定义该细胞器适应慢性疾病需求的能力的机械瓶颈。从该平台出现的技术，方法和模型将产生对ER生物学的重要见解，并将为各种慢性复杂疾病提供应用。 公共卫生相关性：慢性代谢疾病，例如肥胖，胰岛素抵抗，2型糖尿病和心血管疾病，是对全球健康的不利影响的最常见疾病。尽管对人类生活负担巨大，但预防和治疗机会是有限的，并且需要新的和更有效的补救措施。我们的项目旨在通过关注代谢性疾病中有机器功能障碍的新兴和令人兴奋的概念来确定引起这些病理的核心机制。在此提案中，我们将研究重点放在内质网上的细胞器衰竭的原因，并使用系统的高通量方法来鉴定来自对照和疾病影响组织的纯化细胞器中所有调节的脂质和蛋白质。通过这些实验发现的机制将在预防和治疗策略的设计和实施中发挥作用，并允许通用野外试剂和技术探索养分暴露的生物学作用和机制。拟议的研究与该计划的几个主题非常匹配。