Deconvolution of adaptive metabolic responses of the endoplasmic reticulum

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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.