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一氧化氮和健康和疾病中氧化剂产生失衡的原因和后果，研究免疫系统的微生物杀伤机制，研究细胞中的金属稳态及其在细胞中的细胞分化中的氧化还原相关性的有助于细胞的相关性。目前，良好的是，氧化稳态和电子转移反应是维持健康生理过程的基础，并且它们的障碍或功能障碍会导致严重的表型后果。氧化剂的生物利用度降低或过量产生和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损害或细胞和组织损伤诱导者损害的关键因素。氧化剂失衡已成为糖尿病，动脉粥样硬化，炎症，男性阳性以及有助于干细胞分化，再生以及癌症发作，进展和预后的重要因素，成为高血压和心血管并发症的公认因素。所有这些都是人类的公共健康利益条件。伊利诺伊大学的芝加哥医学，牙科，药房和生物科学通过其多元化部门和研究计划目前正在开发多种研究和计划，致力于理解如何通过使用EPR来跟踪，识别和量化EPR的使用，通过使用EPR来使用EPR的使用来增加炎症和SEPIS氧化的肺部变化，氧化不足的氧化能力，使氧化不良的氧化能力变化，氧化不良，氧化不良，氧化不良，氧化不良的氧化能力变化。以及损伤，干细胞分化，蛋白质相互作用，癌症生物学，光合作用，微生物杀伤和药物代谢。此类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中的哪种能力，以及对反应性物种产量的精确定量，这是我们定义电子供体和受体的能力，并跟踪分子事件，从而影响膜的渗透性和与药物的相互作用。电子顺磁共振（EPR）仍然是唯一能够基于指纹签名谐振光谱的特殊识别特定的顺磁性物种（稳定和短寿命）的可用技术，并实现了量化自由基氧化剂的产生的目的。例如，直接识别超氧化物自由基阴离子和一氧化氮的来源至关重要，这些氧化物和一氧化氮有助于炎症和触发信号事件的组织损伤，从而导致肺水肿，高血压和心脏衰竭或触发事件（例如干细胞分化）。同时，有可能确定超氧化物歧化酶如何避免或促进氧化应激事件有必要或损害一氧化氮的生物利用度。通过自旋标记，可以研究膜微域形成并跟踪药物代谢产物。因此，对EPR工具的获取将融合并独特地为当前倡议的发展做出贡献，同时促进新的合作研究，使部门能够在理解复杂的分子过程和开发疗法的发展方面取得重要的进步，并在细胞层面重新平衡生理过程。