Deconvolution of adaptive metabolic responses of the endoplasmic reticulum

描述（由申请人提供）：本提案中涉及的研究领域涉及系统方法，以探索引起慢性代谢性疾病（如肥胖症、糖尿病和心血管疾病）的机制，并对癌症和其他退行性疾病产生影响。这一疾病群目前构成最具破坏性的全球卫生问题，预计在今后25年将继续以惊人的速度增长。因此，我们的建议与“关注全球卫生”高度相关。此外，我们系统地解码慢性代谢疾病中细胞器特异性蛋白质和脂质景观的方法也与研究主题“应用基因组学和其他高通量技术”有关，该项目的成果将成为利用细胞器治疗作为筛选和开发治疗方法的新平台的强有力的指导和资源，这与该倡议的转化目标一致。我们的研究受到最近出现的证据的启发，这些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行性疾病，都具有细胞器功能障碍，特别是线粒体和内质网。然而，目前对这些病理状况如何与细胞器功能障碍相关以及这些细胞器的慢性衰竭如何导致这些病理的发展几乎没有了解。在理解慢性细胞器适应方面的这些主要差距，或缺乏这些差距，限制了对预防和治疗使人衰弱的慢性疾病的新途径和可能性的开发。在这个项目中，我们建议专注于内质网和系统地研究这个细胞器和它的功能输出，使用细胞器特异性蛋白质组学，脂质组学，ER相关的多聚核糖体分析和分析的综合平台，以确定所有的翻译输出的多聚核糖体受到调节，以及在代谢疾病的背景下的功能扰动。我们的方法不假设任何关于这个细胞器的内稳态的先验偏差，并且旨在以全面的方式解决导致其失败的机制，而不仅仅限于这个细胞器在蛋白质合成，折叠和代谢中的公认功能。我们相信，这一新的新兴领域提供了巨大的机会，翻译的可能性，并保证系统的方法来定义这个细胞器的能力，以适应慢性疾病的需求的机制瓶颈。从这个平台出现的技术，方法和模型将产生对ER生物学的重要见解，并将应用于广泛的慢性复杂疾病。 公共卫生相关性：慢性代谢性疾病，如肥胖、胰岛素抵抗、2型糖尿病和心血管疾病，是对全球健康产生不利影响的最常见疾病。尽管它们对人类生活造成巨大负担，但预防和治疗机会有限，并且不断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疾病中细胞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。在这项提案中，我们将研究细胞器失败的原因，重点是内质网和使用系统的高通量方法来确定所有受调节的脂质和蛋白质在纯化的细胞器从控制和疾病折磨的组织。通过这些实验发现的机制将有助于预防和治疗策略的设计和实施，并允许一般的现场试剂和技术来探索营养素暴露的生物效应和机制。拟议的研究与倡议的几个主题非常吻合。

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.