Mechanisms of mitochondrial-ER communication during dietary and thermal induced stress

饮食和热应激期间线粒体-内质网通讯的机制

基本信息

批准号：
10663603
负责人：
Pedro Antonio Latorre Muro
金额：
$ 9万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663603
关键词：
Adipocytes Adipose tissue Adrenergic Agents Adrenergic Receptor Affect Amino Acids Award Binding Biochemical Bioenergetics Biogenesis Blood Glucose Body Weight CRISPR/Cas technology Cardiovascular Diseases Cell Respiration Cell physiology Cellular biology Client Collaborations Communication Communities Complex Country Crista ampullaris Cryoelectron Microscopy Dana-Farber Cancer Institute Data Development Development Plans Diabetes Mellitus Diet Disease Endoplasmic Reticulum Energy Metabolism Ensure Environment Epidemic Equilibrium Event Exercise Experimental Designs Exposure to Fatty Acids Fatty Liver Fatty acid glycerol esters Future Glucose Goals Health Heat-Shock Proteins 70 Heat-Shock Proteins 90 High Fat Diet Homeostasis In Vitro Individual Inflammation Institution Insulin Resistance Knockout Mice Knowledge Laboratories Liver Long-Term Effects LoxP-flanked allele Malignant Neoplasms Manuscripts Mass Spectrum Analysis Membrane Mentorship Metabolic Diseases Metabolism Microscope Mitochondria Mitochondrial Proteins Modeling Molecular Molecular Chaperones Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Nuclear Proteins Obesity Organ Organelles Outcome PERK kinase Pathway interactions Phase Physiology Population Preparation Protein Import Protein Precursors Receptor Signaling Regulation Regulatory Element Research Research Personnel Risk Role SARS-CoV-2 infection Sampling Shapes Signal Pathway Signal Transduction Skeletal Muscle Stress Students Thermogenesis Training Weight Gain Work acid stress age related blood glucose regulation bone career development diet-induced obesity dietary dietary control energy balance fatty acid oxidation follow-up improved in vivo insulin sensitivity medical schools mouse model novel novel therapeutic intervention pandemic disease protein complex protein function research and development response skills stressor structural biology sugar therapeutic target thermal stress tool

项目摘要

Project Summary/Abstract Obesity is a pandemic affecting 40% of the population that increases the risk of serious metabolic diseases including type 2 diabetes and severe forms of SARS-CoV2 infection. Obesity reduces insulin sensitivity and dysregulates glucose homeostasis sustaining high blood glucose levels and the development of type 2 diabetes. Activation of brown adipocytes (BAs) is a promising approach to treat obesity and associated diseases. Brown adipocytes rely on an extensive network of mitochondria that increases energy expenditure and maintains glucose homeostasis through glucose, amino acid, and fatty acid oxidation. During fat-induced stress, mitochondrial-endoplasmic reticulum (ER) communication sustains cellular function in BAs. However, the mechanisms by which mitochondrial-ER communication shapes cellular adaptation during obesity are poorly understood. Therefore, studying these pathways will provide new therapeutical approaches to target obesity. The main goal of this application is to study the mechanisms of mitochondrial-ER communication that ensure mitochondrial function and cellular homeostasis during diet-induced stress. We have described that in BAs mitochondrial-ER communication promotes thermogenesis during cold stimulation through the ER-resident kinase PERK. To follow up this work, in Aim 1, the effects of long-term high fat diet (HFD) will be studied in UCP1-Cre PERK-/- mice exposed to different dietary and bioenergetic conditions. Our preliminary information suggests that PERK may be signaling to the chaperone PPID to control mitochondrial protein import. In Aim 2, structural approaches using Cryogenic Electron Microscopy (CryoEM) will be used to explore the molecular interactions that control and maintain mitochondrial functions in BAs including mitochondrial protein import, focusing on PPID-dependent pathway, and cellular respiration during dietary and thermal stress. Finally, in Aim 3 the role of PPID in physiology and cellular functions will be studied in mice exposed to diet and thermal stress. While Aims 1 and part of 2 will be completed during the training stage, part of Aim 2 and the entire Aim 3 will be conducted during the independent phase of the award. The extensive training in different fields proposed in this application including physiology and cellular and structural biology will provide the tools to become an independent researcher and study the mechanisms of inter- organalle communication that regulate mitochondrial biogenesis and cellular metabolism. This training will be received in the vibrant scientific communities of Dana-Farber Cancer Institute and Harvard Medical School. This environment will expose me to the collaborations and discussions necessary for career development and future opportunities. Dr. Puigserver mentorship will be supportive to establish those connections and actively guide me in talk and manuscript preparation, student mentorship, experimental design, and career development. Together, the research and career development plans proposed in this application will strengthen my skills and competitiveness to become an independent researcher at a major institution.

项目概要/摘要肥胖是一种流行病，影响了 40% 的人口，增加了患严重代谢疾病的风险包括 2 型糖尿病和严重的 SARS-CoV2 感染。肥胖会降低胰岛素敏感性葡萄糖稳态失调，维持高血糖水平和 2 型糖尿病的发展。棕色脂肪细胞（BA）的激活是治疗肥胖及相关疾病的一种有前途的方法。棕色的脂肪细胞依赖于广泛的线粒体网络来增加能量消耗并维持通过葡萄糖、氨基酸和脂肪酸氧化维持葡萄糖稳态。在脂肪引起的压力下，线粒体-内质网 (ER) 通讯维持 BA 中的细胞功能。然而，肥胖期间线粒体-内质网通讯塑造细胞适应的机制很差明白了。因此，研究这些途径将为针对肥胖提供新的治疗方法。该应用的主要目标是研究线粒体-ER 通讯的机制，以确保饮食引起的应激期间的线粒体功能和细胞稳态。我们已经在 BA 中描述了这一点线粒体-内质网通讯通过内质网驻留促进冷刺激期间的产热激酶 PERK。为了跟进这项工作，在目标 1 中，将研究长期高脂肪饮食 (HFD) 的影响 UCP1-Cre PERK-/- 小鼠暴露于不同的饮食和生物能条件。我们的初步信息表明 PERK 可能向伴侣 PPID 发出信号以控制线粒体蛋白输入。在目标 2 中，使用低温电子显微镜（CryoEM）的结构方法将用于探索分子控制和维持 BA 中线粒体功能的相互作用，包括线粒体蛋白输入，重点关注 PPID 依赖性途径以及饮食和热应激期间的细胞呼吸。最后，在目标 3 将在暴露于饮食和热应激的小鼠中研究 PPID 在生理学和细胞功能中的作用。目标 1 和目标 2 的一部分将在训练阶段完成，而目标 2 的一部分和整个目标 3 将在训练阶段完成。在颁奖的独立阶段进行。本申请中提出的不同领域的广泛培训，包括生理学和细胞学以及结构生物学将提供成为独立研究者和研究相互作用机制的工具调节线粒体生物发生和细胞代谢的细胞器通讯。此次培训将获得了达纳法伯癌症研究所和哈佛医学院充满活力的科学界的认可。这环境将使我能够接触到职业发展和未来所需的合作和讨论机会。 Puigserver 博士的指导将支持我建立这些联系并积极指导我演讲和手稿准备、学生指导、实验设计和职业发展。一起，本申请中提出的研究和职业发展计划将增强我的技能和成为主要机构的独立研究员的竞争力。