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Thomas W. Sedlak, m.d., Ph.D.，是约翰霍普金斯医学院精神病学系的临床研究员。他的长期职业目标是成为一名独立的研究科学家，开展神经保护机制的研究，以改善神经精神疾病。为了实现这一目标，他制定了一项指导研究职业发展计划，提供神经科学技术，氧化应激，分子成像以及钙和一氧化氮信号的培训。细胞死亡和功能障碍是各种脑部疾病的共同终点，增强对衰老和神经退行性疾病压力的抵抗力是改善人类卫生保健的长期目标。本提案的目的是表征血红素加氧酶/胆绿素还原酶途径的细胞保护功能，该途径利用血红素形成胆红素。虽然胆红素曾经被认为是唯一有害的代谢副产物，但它越来越被认为是一种有效的抗氧化剂，可以在生理浓度下消除细胞死亡。许多临床研究表明，血清胆红素水平的轻度升高与脑血管疾病和冠状动脉疾病等疾病的预后改善有关。我们的长期目标是将血红素加氧酶/胆绿素还原酶/胆红素途径应用于神经精神疾病模型。为了实现这一目标，本研究的目标是表征这一途径的调控，以及受其保护的细胞成分。谷胱甘肽被认为是一种基本的细胞保护剂，我们假设胆红素具有补充功能。具体来说，胆红素可能优先保护细胞脂质，而谷胱甘肽则保护细胞蛋白，两者在保护DNA方面都有共同的职责。此外，我们试图描述细胞调节这一保护途径的方式，之前已经证明钙/钙调蛋白是神经传递的重要组成部分，激活血红素加氧酶-2，这是大脑中胆红素产生的第一步。我们现在将描述钙/钙调素在调节胆红素还原酶中的作用，胆红素还原酶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，我们将描述其对胆绿素还原酶活性和细胞保护的影响。具体来说，假设一氧化氮靶向胆绿素还原酶的半胱氨酸残基，以增加其酶活性和细胞保护功能。提高对细胞胆红素产生的理解可以指导神经退行性和神经精神疾病以及氧化细胞损伤的合理治疗设计。