The New Family of NEET Proteins: 2Fe-2S Protein Mediated Health and Disease

NEET 蛋白新家族：2Fe-2S 蛋白介导的健康和疾病

• 批准号: 8276257
• 负责人: PATRICIA A JENNINGS
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8276257
• 关键词: 2,4-thiazolidinedione; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Area; Autophagocytosis; Binding; Binding Sites; Biochemical; Biochemical Process; Biological; Blood Glucose; Cell Death Process; Cell Survival; Central obesity; Cognitive; Complex; Coronary artery; Defect; Diabetes Mellitus; Disease; Drug Design; Electron Transport; Endoplasmic Reticulum; Epidemic; Family; Future; Goals; Health; Homologous Gene; Human; Hypertension; In Vitro; Inflammation; Investigation; Iron; Lead; Limb structure; Longevity; Malignant Neoplasms; Mediating; Metabolic syndrome; Mitochondria; Mitochondrial Proteins; Molecular; Multiple Sclerosis; Mutation; Natural Product Drug; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Obesity associated disease; Optic Atrophy; Outer Mitochondrial Membrane; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathology; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pioglitazone; Play; Premature aging syndrome; Property; Protein Binding; Protein Family; Protein S; Proteins; Regulation; Reporting; Resveratrol; Role; Structure; Therapeutic Intervention; Thiazolidinediones; Thinking; Wolfram Syndrome; World Health; computer studies; deafness; drug candidate; drug development; early onset; insulin sensitizing drugs; interest; new therapeutic target; novel; novel therapeutics; oxidation; protein protein interaction; small molecule; transcription factor

DESCRIPTION (provided by applicant): The rise in obesity worldwide parallels a dramatic increase in obesity-associated diseases, most notably type-II diabetes. This disease is predicted to reach epidemic proportions in the next several decades. Thus, understanding the biochemical processes underlying type-II diabetes and identifying new targets for therapeutic intervention are critical for national and world health. Some of the most widely prescribed insulin-sensitizing drugs to treat type-II diabetes belong to the thiazolidinedione (TZD) class of molecules. These drugs were found to also reduce many of the pathologies related to metabolic syndrome including hypertension, abdominal obesity, coronary artery inflammation, multiple sclerosis, Alzheimer's disease and Amyotrophic lateral sclerosis. While the TZDs were originally thought to exert their effects solely through activation of the nuclear transcription factor PPAR¿, it is nw known that many of the beneficial effects are mediated in a PPAR¿-independent manner. The TZDs were recently shown to interact with a novel mitochondrial protein target called mitoNEET. We reported that the protein mitoNEET is a redox-active, pH-labile 2Fe-2S cluster containing protein in the outer mitochondrial membrane. This is the only known Fe-S protein in the outer mitochondrial membrane. In addition, we discovered that MitoNEET plays an important role in iron management under oxidative stress conditions. Miner1, an endoplasmic reticulum homolog of mitoNEET, is important in maintaining health and longevity and interacts with proteins associated with cancer as well as neurodegenerative diseases. These proteins have emerged as important new therapeutic targets in diseases ranging from diabetes to Alzheimer's. The focus of this proposal is the structural, biochemical and functional characterization of this novel protein family. Specifically, we are investigating the molecular determinants of drug binding as a function of changes in oxidation state and asking how drug binding impacts newly discovered protein-protein interactions that are involved in regulating cell survival and death processes. The proposed studies are of both fundamental significance in understanding this protein-drug recognition as well as the identification of novel therapeutics. PUBLIC HEALTH RELEVANCE: Every thirty seconds someone loses a limb/ limb function as a result of complications from unregulated blood glucose levels. Complications associated with the traditional anti-diabetes targeted therapies underscores the need for a paradigm shift in thinking with respect to new drug development. The goals of this proposal are directed towards the structural/biochemical characterization of drug binding to the newly discovered anti- diabetes targets: the novel 2Fe-2S proteins MitoNEET and Miner1.

描述（由申请人提供）：全球肥胖症的增加与肥胖相关疾病的急剧增加相平行，最明显的是II型糖尿病。据预测，这种疾病在今后几十年内将达到流行病的程度。因此，了解II型糖尿病的生化过程并确定治疗干预的新目标对国家和世界健康至关重要。治疗II型糖尿病的一些最广泛处方的胰岛素增敏药物属于噻唑烷二酮（TZD）类分子。发现这些药物还减少许多与代谢综合征相关的病理，包括高血压、腹部肥胖、冠状动脉炎症、多发性硬化、阿尔茨海默病和肌萎缩侧索硬化。虽然TZDs最初被认为仅通过激活核转录因子PPAR发挥其作用，但目前已知许多有益作用是以不依赖PPAR的方式介导的。TZDs最近被证明与一种名为mitoNEET的新型线粒体蛋白质靶点相互作用。我们报道了蛋白mitoNEET是一个氧化还原活性，pH不稳定的2Fe-2S簇包含在线粒体外膜蛋白。这是线粒体外膜中唯一已知的Fe-S蛋白。此外，我们发现MitoNEET在氧化应激条件下的铁管理中起着重要作用。Miner 1是mitoNEET的内质网同源物，在维持健康和长寿方面很重要，并与癌症和神经退行性疾病相关的蛋白质相互作用。这些蛋白质已经成为从糖尿病到阿尔茨海默氏症等疾病的重要新治疗靶点。该提案的重点是该小说的结构、生化和功能表征 蛋白质家族具体来说，我们正在研究药物结合的分子决定因素作为氧化态变化的函数，并询问药物结合如何影响新发现的蛋白质-蛋白质相互作用，这些相互作用参与调节细胞存活和死亡过程。的 所提出的研究对于理解这种蛋白质-药物识别以及鉴定新的治疗剂都具有根本的意义。 公共卫生相关性：每30秒就有一个人由于血糖水平不受控制的并发症而失去肢体/肢体功能。与传统抗糖尿病靶向疗法相关的并发症凸显了新药开发思维范式转变的必要性。该提案的目标是针对与新发现的抗糖尿病靶点结合的药物的结构/生物化学表征：新型2Fe-2S蛋白MitoNEET和Miner 1。