Oxidative stress imbalance n Pulmonary&Cardiovascular disease,Electron paramagnet

肺氧化应激失衡

• 批准号: 8052669
• 负责人: Marcelo G Bonini
• 金额: $ 25.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-02 至 2012-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052669
• 关键词: Anions; Atherosclerosis; Biological Availability; Biological Sciences; Cancer Biology; Cardiovascular Diseases; Cardiovascular system; Cell Membrane Permeability; Cell Proliferation; Cells; Chicago; Dentistry; Development; Diabetes Mellitus; Disease; Disease Progression; Electron Spin Resonance Spectroscopy; Electron Transport; Electrons; Enzymes; Event; Fingerprint; Fostering; Free Radicals; Functional disorder; Generations; Health; Heart failure; Homeostasis; Human; Hypertension; Illinois; Immune system; Impairment; Impotence; Inflammation; Lead; Life; Lung; Malignant Neoplasms; Mediating; Medicine; Membrane Microdomains; Metals; Molecular; Natural regeneration; Nitric Oxide; Nitrogen; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen; Permeability; Pharmaceutical Preparations; Pharmacy facility; Photosynthesis; Physiological Processes; Positioning Attribute; Process; Production; Proteins; Public Health; Pulmonary Edema; Reaction; Research; Sepsis; Signal Transduction; Source; Spin Labels; Staging; Superoxide Dismutase; Superoxides; Techniques; Time; Tissues; Universities; Vascular remodeling; Ventricular Function; base; cell motility; college; drug metabolism; electron donor; instrument; interest; killings; male; microbial; outcome forecast; programs; stem cell differentiation; therapy development

DESCRIPTION (provided by applicant): The overall objective of this research effort is to identify the causes and consequences of nitric oxide and oxidant production imbalances in health and disease, investigate mechanisms of microbial killing by the immune system, study metal homeostasis in cells and how it contributes to cellular proliferation and migration and establish the relevance of redox processes in the differentiation of stem cells. It is currently well-established that oxidant homeostasis and electron transfer reactions are fundamental in maintaining physiological processes in health and that their impairment or dysfunction cause severe phenotypical consequences. Both reduced oxidant bioavailability or overproduction and difficulties in mediating key electron transfer reactions are key factors leading to the impairment of beneficial signal transduction events or inducers of cellular and tissue damage. Oxidant imbalances are becoming recognized contributors of hypertension and cardiovascular complications in diabetes, atherosclerosis, inflammation, male impotence, and important factors contributing to stem cell differentiation and regeneration and cancer onset, progression and prognosis. All of these are human conditions of public health interest. The University of Illinois at Chicago Colleges of Medicine, Dentistry, Pharmacy and Biological Sciences through its diverse departments and research initiatives is currently developing multiple studies and programs dedicated to the understanding of how paramagnetic species that can be tracked, identified and quantified through the use of EPR lead to increased lung permeability in inflammation and sepsis, oxidative stress induced alterations of ventricular function, oxidant mediated vascular remodeling and damage, stem cell differentiation, protein interactions, cancer biology, photosynthesis, microbial killing and drug metabolism. The development of such initiatives depend, at least in part, on our ability to identify which among the many reactive oxygen and nitrogen species are produced at different stages of disease progression, and the precise quantification of reactive species yield, on our capacity to define electron donors and acceptors and track molecular events influencing membrane permeability and interaction with drugs. Electron paramagnetic resonance (EPR) remains the only available technique capable of unequivocally identifying particular paramagnetic species (stable and short lived) based on fingerprint signature resonance spectra and serves the purpose of quantifying the generation of free radical oxidants. For example, it is of pivotal importance to directly identify the sources of superoxide radical anion and nitric oxide that contribute to tissue damage in inflammation and trigger signaling events that contribute to pulmonary edema, hypertension and cardiac failure or trigger events such as stem cell differentiation. At the same time it would be possible to determine how superoxide dismutase enzymes contribute to avoid or promote oxidative stress events warranting or compromising nitric oxide bioavailability. Through spin labeling it would be possible to study membrane microdomain formation and track drug metabolites. Therefore, the acquisition of an EPR instrument would integrate and uniquely contribute for the development of the current initiatives while fostering new collaborative studies putting the departments in the position of making important progress towards the understanding of intricate molecular processes and the development of therapies to re-equilibrate physiological processes at the cellular level.

描述（由申请人提供）：这项研究工作的总体目标是确定健康和疾病中一氧化氮和氧化剂产生不平衡的原因和后果，研究免疫系统杀死微生物的机制，研究细胞中的金属稳态以及如何它有助于细胞增殖和迁移，并建立氧化还原过程在干细胞分化中的相关性。目前已明确，氧化剂稳态和电子转移反应是维持健康生理过程的基础，它们的损伤或功能障碍会导致严重的表型后果。氧化剂生物利用度的降低或过量产生以及介导关键电子转移反应的困难都是导致有益信号转导事件或细胞和组织损伤诱导物受损的关键因素。氧化失衡已成为公认的高血压和糖尿病心血管并发症、动脉粥样硬化、炎症、男性阳痿的促成因素，也是促进干细胞分化和再生以及癌症发生、进展和预后的重要因素。所有这些都是涉及公共卫生利益的人类状况。伊利诺伊大学芝加哥分校医学院、牙科学院、药学学院和生物科学学院通过其不同的院系和研究计划目前正在开展多项研究和项目，致力于了解如何通过使用EPR 导致炎症和脓毒症中肺通透性增加、氧化应激诱导的心室功能改变、氧化剂介导的血管重塑和损伤、干细胞分化、蛋白质相互作用、癌症生物学、光合作用、微生物杀灭和药物新陈代谢。这些举措的发展至少部分取决于我们确定在疾病进展的不同阶段产生的许多活性氧和氮物种的能力，以及活性物种产量的精确量化，取决于我们定义电子的能力供体和受体并跟踪影响膜通透性和与药物相互作用的分子事件。电子顺磁共振 (EPR) 仍然是唯一能够根据指纹特征共振光谱明确识别特定顺磁性物质（稳定和短命）的可用技术，并用于量化自由基氧化剂的生成。例如，直接识别超氧自由基阴离子和一氧化氮的来源至关重要，它们会导致炎症中的组织损伤，并触发导致肺水肿、高血压和心力衰竭的信号事件或触发干细胞分化等事件。同时，可以确定超氧化物歧化酶如何有助于避免或促进保证或损害一氧化氮生物利用度的氧化应激事件。通过自旋标记，可以研究膜微区的形成并追踪药物代谢物。因此，购买 EPR 仪器将整合并独特地促进当前举措的发展，同时促进新的合作研究，使各部门在理解复杂的分子过程和开发治疗方法方面取得重要进展。在细胞水平上平衡生理过程。