TRPA1 Physiology in Diabetes, Metabolic Syndrome, and Metabolism

TRPA1 糖尿病、代谢综合征和代谢的生理学

基本信息

批准号：
9211067
负责人：
Alexander James Stokes
金额：
$ 23.1万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211067
关键词：
Abdomen Address Antibodies Beta Cell Binding Proteins Bioavailable Biochemical Biological Assay Blood Pressure Calcium Cannabinoids Cardiovascular Diseases Cations Cell Fractionation Cell membrane Cell physiology Cells Centers of Research Excellence Central obesity Chemicals Chronic Complex Coupling Creatine Kinase Data Development Diabetes Mellitus Disease Disease Outcome Electrophysiology (science)Endocrine Enzymes Epidemic Excision Exhibits Fasting Functional disorder Generations Geography Healthcare Heritability High Density Lipoproteins High Fat Diet Human Hyperglycemia Hyperinsulinism Hypertension In Vitro Instruction Insulin Insulin Resistance Isoenzymes Kidney Knock-out Knowledge Laboratories Ligands Link Maintenance Mediating Membrane Potentials Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Mitochondria Modeling Molecular Mutation Nutrient Obesity Online Mendelian Inheritance In Man Oral Outcome Output Oxidation-Reduction Oxygen Pain Pancreas Pancreatectomy Pathology Patients Pharmacology Pharmacopoeias Physiological Physiology Process Production Proteins Publishing Pyruvate Dehydrogenase Complex Quality of life Regulation Resources Serum Severities Signal Transduction Small Interfering RNA Sodium Chloride Stimulus Streptozocin Structure of beta Cell of islet System TRPA1 Channel Techniques Temperature Tissues Translating Triglycerides Universities Whole Organism chemical property exhaustion fasting plasma glucose in vivo in vivo Model knock-down knockout gene mitochondrial membrane mouse model novel pre-clinical protein protein interaction pyruvate dehydrogenase receptor release of sequestered calcium ion into cytoplasm research clinical testing response small molecule socioeconomics therapeutic target tool translational approach

Abdomen Address Antibodies Beta Cell Binding Proteins Bioavailable Biochemical Biological Assay Blood Pressure Calcium Cannabinoids Cardiovascular Diseases Cations Cell Fractionation Cell membrane Cell physiology Cells Centers of Research Excellence Central obesity Chemicals Chronic Complex Coupling Creatine Kinase Data Development Diabetes Mellitus Disease Disease Outcome Electrophysiology (science)Endocrine Enzymes Epidemic Excision Exhibits Fasting Functional disorder Generations Geography Healthcare Heritability High Density Lipoproteins High Fat Diet Human Hyperglycemia Hyperinsulinism Hypertension In Vitro Instruction Insulin Insulin Resistance Isoenzymes Kidney Knock-out Knowledge Laboratories Ligands Link Maintenance Mediating Membrane Potentials Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Mitochondria Modeling Molecular Mutation Nutrient Obesity Online Mendelian Inheritance In Man Oral Outcome Output Oxidation-Reduction Oxygen Pain Pancreas Pancreatectomy Pathology Patients Pharmacology Pharmacopoeias Physiological Physiology Process Production Proteins Publishing Pyruvate Dehydrogenase Complex Quality of life Regulation Resources Serum Severities Signal Transduction Small Interfering RNA Sodium Chloride Stimulus Streptozocin Structure of beta Cell of islet System TRPA1 Channel Techniques Temperature Tissues Translating Triglycerides Universities Whole Organism chemical property exhaustion fasting plasma glucose in vivo in vivo Model knock-down knockout gene mitochondrial membrane mouse model novel pre-clinical protein protein interaction pyruvate dehydrogenase receptor release of sequestered calcium ion into cytoplasm research clinical testing response small molecule socioeconomics therapeutic target tool translational approach

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项目摘要

Abstract Pancreatic function is central to Metabolic Syndrome (MS) and patients exhibit long-term hyperinsulinemia as the pancreas compensates for nutrient overload through insulin over-production. Beta cell exhaustion, insulin resistance and diabetes follow this chronic hyperinsulinemia. Transient Receptor Potential (TRP) cation channels are druggable targets in several sequelae of the MS (e.g., cardiovascular disease), and TRPA1 has recently been directly implicated in the pancreatic dysfunction underlying MS. Recent studies show that TRPA1 conducts Ca2+ to controls insulin release in the pancreas, offering TRPA1 as a therapeutic target for regulation of insulin output. TRPA1 is best understood as nocioceptive channel. An intriguing human heritable mutation in TRPA1 (OMIM: 615040) causes serious episodic pain in response to fasting, establishing another link between TRPA1 and metabolism. However, significant knowledge gaps remain concerning (1) the mechanistic basis for coupling of metabolic/endocrine inputs to TRPA1 activity, and (2) whether pharmacological regulation of TRPA1 translates to modulation of metabolic pathways in whole organisms. Our new preliminary data validate expression of TRPA1 in the pancreas, and other tissues, and directly link TRPA1 to metabolism and mitochondria. Three independent techniques (EM, IF and subcellular fractionation) show that TRPA1 localizes to mitochondria (Mt). Moreover, we demonstrate interactions between endogenous TRPA1 and all isoenzymes of creatine kinase (CK), plus pyruvate dehydrogenase (PDH) subunits. Strikingly, the former inhibit TRPA1 channel activity, indicating that TRPA1 is regulated by metabolic enzymes. These findings suggest TRPA1 transduces the effects of its activators (temperature, Ca2+, O2, and pungent compounds) into metabolic pathways, linking directly to mitochondrial processes and status. These findings raise new questions that will be addressed in three Specific Aims, enabled by a comprehensive set of TRPA1 modulators, antibodies, and in vivo knockout and gene editing tools available in the PI's laboratory. These questions are: What is the mechanistic basis for coupling of pancreatic beta cell function to TRPA1 activity, does this critically involve Creatine Kinase or PDH? (Aim 1); Where does this regulation and functional contribution to beta cell function reside, in the plasma membrane, mitochondria, and in other tissues than the pancreas? (Aim 2); and Does pharmacological regulation of TRPA1 translate to modulation of metabolic pathways and disease outcomes at the whole organism level? (Aim 3).

抽象的胰腺功能是代谢综合征（MS）的核心，患者表现出长期的高胰岛素血症胰腺可以通过胰岛素过量生产来补偿养分超负荷。 β细胞耗尽，胰岛素耐药性和糖尿病遵循这种慢性高胰岛素血症。瞬态受体电位（TRP）阳离子通道是MS后遗症（例如心血管疾病）的几个后遗症中的可药靶标的，TRPA1具有最近直接与MS的胰腺功能障碍有关。最近的研究表明TRPA1 将Ca2+用于控制胰腺中的胰岛素释放，并提供TRPA1作为调节的治疗靶标胰岛素输出。最好将TRPA1理解为Nocioceptive渠道。一个有趣的人类遗传突变 TRPA1（OMIM：615040）响应禁食，引起严重的情节疼痛，建立了另一个联系 TRPA1和代谢。但是，（1）代谢/内分泌输入与TRPA1活性的偶联，（2）药理学调节是否是否 TRPA1转化为整个生物中代谢途径的调节。我们新的初步数据验证胰腺和其他组织中TRPA1的表达，并直接连接 TRPA1代谢和线粒体。三种独立技术（EM，IF和亚细胞分级分级）证明TRPA1本地化为线粒体（MT）。此外，我们展示了内源性之间的相互作用 TRPA1和肌酸激酶（CK）的所有同工酶，以及丙酮酸脱氢酶（PDH）亚基。令人惊讶的是，前者抑制TRPA1通道活性，表明TRPA1受代谢酶调节。这些调查结果表明TRPA1会导致其激活剂的效果（温度，Ca2+，O2和辛辣化合物）成代谢途径，直接链接到线粒体过程和状态。这些发现提出新的问题，这些问题将在三个特定目标中解决，这是由一组TRPA1组成的 PI实验室可用的调节剂，抗体和体内敲除和基因编辑工具。这些问题是：胰腺β细胞函数与TRPA1活性的耦合的机理基础，这至关重要的是肌酸激酶或PDH吗？（目标1）;这个法规和功能性在哪里对Beta细胞功能的贡献，存在于质膜，线粒体和其他组织中胰腺？（目标2）;并且TRPA1的药理调节转化为代谢的调节整个生物体的途径和疾病结局？（目标3）。