Cell signaling and cytoprotective roles of biliverdin reductase

胆绿素还原酶的细胞信号传导和细胞保护作用

• 批准号: 7472654
• 负责人: Thomas William Sedlak
• 金额: $ 17.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472654
• 关键词: Aging; Alzheimer' s Disease; Animals; Antioxidants; Apoptosis; Bilirubin; Biliverdin reductase; Binding; Biology; Brain; Brain Diseases; Calcium; Calmodulin; Cell Death; Cell model; Cells; Cerebrovascular Disorders; Clinical; Clinical Research; Condition; Coronary Arteriosclerosis; Cysteine; Cytoprotection; Cytoprotective Agent; DNA; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Elevation; End Point; Enzymes; Exhibits; Functional disorder; Glutathione; Goals; Healthcare; Heme; Hippocampus (Brain); Human; Knowledge; Link; Lipids; Major Depressive Disorder; Mentors; Metabolic; Modeling; Molecular Target; NOS1 protein, human; Nerve Degeneration; Neurons; Neurosciences; Nitric Oxide; Numbers; Outcome; Oxidative Stress; Oxidoreductase; Oxygenases; Parkinson Disease; Pathway interactions; Personal Satisfaction; Physiological; Play; Predisposition; Production; Proteins; Psychiatry; RNA Interference; Regulation; Research; Resistance; Role; Scientist; Serum; Signal Pathway; Signal Transduction; Stress; Techniques; Thinking; Training; Water; Work; career; cellular targeting; heme oxygenase-2; improved; knockout animal; medical schools; molecular imaging; neurogenesis; neuropsychiatry; neurotransmission; oxidation; protein protein interaction; relating to nervous system; resilience; therapy design

DESCRIPTION (provided by applicant): The candidate, Thomas W. Sedlak, M.D., Ph.D., is a clinical fellow in the Department of Psychiatry at Johns Hopkins School of Medicine. His long-term career goal is to become an independent research scientist carrying out research on neuroprotective mechanisms that will ameliorate neuropsychiatric disease. To realize this goal, he has developed a mentored research career development plan that provides training in techniques of neuroscience, oxidative stress, molecular imaging and calcium and nitric oxide signaling. Cell death and dysfunction represent a common end-point for a variety of brain disorders and enhancing resistance to the stresses of aging and neurodegenerative conditions represents a long-term goal in improving human health care. The goal of the present proposal is to characterize the cytoprotective functions of the heme oxygenase/biliverdin reductase pathway, which utilizes heme to form bilirubin. Although bilirubin was once thought to be a solely harmful metabolic byproduct, it is increasingly appreciated as a potent antioxidant that abrogates cell death at physiologic concentrations. A number of clinical studies have linked mild increases in serum bilirubin levels with improved outcomes in conditions such as cerebrovascular disease and coronary artery disease. Our long-term objective is to apply the heme oxygenase/biliverdin reductase/bilirubin pathway to models of neuropsychiatric disease. Towards that objective, the goal of the proposed research is to characterize the regulation of this pathway, as well as the cellular components protected by it. Glutathione is well-appreciated as a fundamental cellular protectant, and we hypothesize that bilirubin serves a complementary function. Specifically, bilirubin may preferentially protect cellular lipids whereas glutathione safeguards cell proteins, each sharing duties in safeguarding DNA. In addition, we seek to characterize the manner in which cells regulate this protective pathway, having previously demonstrated that calcium/calmodulin, an important component of neurotransmission, activates heme oxygenase-2, the first step in bilirubin production in the brain. We will now characterize the role of calcium/calmodulin in regulating biliverdin reductase, the second step in bilirubin production. The gaseous messenger, nitric oxide, also plays a vital role in neurotransmission and cell signaling and we will characterize its impact upon biliverdin reductase activity and cytoprotection. Specifically it is hypothesized that nitric oxide targets cysteine residues of biliverdin reductase to increase its enzymatic activity and cellular protective function. Improved understanding of cellular bilirubin production may guide rational design of treatments for neurodegenerative and neuropsychiatric conditions as well as oxidative cellular damage.

描述（由申请人提供）：候选人，托马斯·W·塞德拉克（Thomas W.他的长期职业目标是成为一名独立的研究科学家，对神经保护机制进行研究，以改善神经精神病。为了实现这一目标，他制定了一项指导的研究职业发展计划，该计划提供了神经科学，氧化应激，分子成像以及钙和一氧化氮信号的技术培训。细胞死亡和功能障碍代表了多种脑疾病的常见终点，并增强对衰老和神经退行性疾病压力的抵抗力代表了改善人类医疗保健的长期目标。本提案的目的是表征血红素氧酶/biliverdin还原酶途径的细胞保护功能，该功能利用血红素形成胆红素。尽管胆红素曾经被认为是一种唯一有害的代谢副产品，但越来越多地认为它是一种有效的抗氧化剂，可消除生理浓度下细胞死亡。许多临床研究已将血清胆红素水平的轻度增加与脑血管疾病和冠状动脉疾病等疾病的预后改善联系在一起。我们的长期目标是将血红素氧酶/双脂蛋白还原酶/胆红素途径应用于神经精神疾病模型。为了实现这一目标，拟议的研究的目标是表征该途径的调节以及受其保护的细胞成分。谷胱甘肽是一种基本的细胞保护剂，被很好地欣赏，我们假设胆红素具有互补功能。具体而言，胆红素可能优先保护细胞脂质，而谷胱甘肽保障细胞蛋白，每种均具有保护DNA的职责。此外，我们试图表征细胞调节该保护途径的方式，此前证明了钙/钙调蛋白是神经传递的重要组成部分，它激活了血红素氧酶-2，这是脑中胆红素生产的第一步。现在，我们将表征钙/钙调蛋白在调节胆红素还原酶的作用，这是胆红素产生的第二步。气态信使一氧化氮在神经传递和细胞信号传导中也起着至关重要的作用，我们将表征其对biliverdin还原酶活性和细胞保护作用的影响。具体而言，假设一氧化氮靶向双列佛蛋白还原酶的半胱氨酸残基，以增加其酶活性和细胞保护功能。对细胞胆红素产生的了解的提高可以指导神经退行性和神经精神病疾病以及氧化性细胞损伤的治疗方法的合理设计。