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CAM Antioxidants and ALS

CAM 抗氧化剂和 ALS

基本信息

批准号：
7902742
负责人：
JOSEPH S BECKMAN
金额：
$ 30.86万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7902742
关键词：
Acetylcarnitine Adopted Affect Age Aging Alzheimer&apos s Disease American American Cancer Society Animal Model Animals Antioxidants Astrocytes Biological Assay Brain Cavia Cell Culture Techniques Cessation of life Chelation Therapy Chronic Chronic Disease Clinical Research Collaborations Communities Complementary and alternative medicine Development Disease Disease Progression Disease model Employee Strikes Environment Enzymes Epidemiologic Studies Epidemiology Funding Goals Hand Health Health Care Costs Heavy Metals Human Incidence Individual Knockout Mice Link Mass Spectrum Analysis Measures Medical Methods Missense Mutation Modeling Molecular Motor Motor Neurons Mus Mutation National Health and Nutrition Examination Survey Nerve Degeneration Neurodegenerative Disorders Newly Diagnosed Oxidation-Reduction Oxidative Stress Parkinson Disease Pathology Patients Pharmaceutical Preparations Population Postpoliomyelitis Syndrome Prevention Primary Prevention Process Proteins Quality of life Rattus Recycling Reporting Research Risk Risk Factors Role Spinal Cord Stress Superoxide Dismutase Support Groups Symptoms Syndrome System Testing Therapeutic Thioctic Acid Tissues Tocopherols Tocotrienols Toxic Actions Toxic effect Transgenic Animals Transgenic Mice Transgenic Organisms Ubiquinone United States National Institutes of Health Vitamin E Work Zinc Zinc deficiency aging brain aging population analytical tool antioxidant therapy ascorbate base copper zinc superoxide dismutase cost dietary antioxidant improved innovation mortality mouse model muscle degeneration mutant nervous system disorder novel nutrition prevent respiratory tool transcription factor

项目摘要

The quality of life of ALS patients has substantially improved in the past decade from better nutrition, respiratory support and a variety of complementary and alternative medicines (CAM). CAM for ALS patients is well accepted by the traditional medical community. Our long-term goal is to find a combination of therapeutic actions to slow the progressive death of motor neurons that defines ALS, turning this fatal disease into a chronic condition resembling post-polio syndrome. An important clue came from discovering mutations to the antioxidant copper, zinc superoxide dismutase cause 2-3% of ALS patients. We found that the loss of zinc from SOD, which is favored by the mutations, is toxic to motor neurons by increasing nitrative stress, suggesting zinc status could link the 2% familial SOD patients with the remaining 98% of ALS patients. Our research has also shown that nitrative stress in astrocytes surrounding motor neurons contributes to the progressive death of motor neurons. Expression of ALS-mutant SODs in transgenic mice and rats is now widely used to study the effects of both traditional as well as CAM therapies on survival. With a better understanding of how SOD malfunctions to cause ALS, we have identified several novel CAM antioxidant therapies that could modulate the progression of ALS. Using a combination of cell culture and microanalytical methods of spinal cord from transgenic rats, we will characterize the ability of CAM therapies to modulate disease progression in these animals. Our first aim is to determine whether zinc can slow the progression of ALS in transgenic SOD rats and whether heavy metal chelation therapy unintentionally may accelerate ALS by removing zinc. Our second aim will characterize whether the depletion of ascorbate by zinc deficient SOD makes the spinal cord vulnerable to a-tocopherol deficiencies. Our final aim will characterize whether lipoic acid can ameliorate the effects of a-tocopherol deficiency or reduce the toxic effects of SOD in aging rats. Our proposed studies will provide a mechanistic basis for examining how CAM antioxidant therapies can be coordinated to modulate the course of ALS.

过去十年，由于营养改善，ALS 患者的生活质量得到了显着改善，呼吸支持和各种补充和替代药物 (CAM)。 ALS 患者的 CAM 被传统医学界广泛接受。我们的长期目标是找到一个组合治疗行动可减缓 ALS 运动神经元的进行性死亡，从而扭转这种致命性疾病转变为类似于脊髓灰质炎后综合症的慢性疾病。一条重要的线索来自于发现抗氧化剂铜、锌超氧化物歧化酶突变导致 2-3% 的 ALS 患者。我们发现 SOD 中锌的损失（突变有利于这种情况）通过增加硝化作用而对运动神经元产生毒性压力，表明锌状态可能将 2% 的家族性 SOD 患者与其余 98% 的 ALS 患者联系起来患者。我们的研究还表明运动神经元周围星形胶质细胞的硝化应激导致运动神经元的进行性死亡。 ALS 突变型 SOD 在转基因小鼠中的表达现在，老鼠被广泛用于研究传统疗法和 CAM 疗法对生存的影响。和为了更好地了解 SOD 故障如何导致 ALS，我们发现了几种新颖的 CAM 抗氧化疗法可以调节 ALS 的进展。结合使用细胞培养和转基因大鼠脊髓的微量分析方法，我们将表征 CAM 疗法的能力调节这些动物的疾病进展。我们的首要目标是确定锌是否可以减缓转基因 SOD 大鼠 ALS 的进展以及重金属螯合疗法是否无意中可能会导致通过去除锌来加速 ALS。我们的第二个目标将表征抗坏血酸的消耗是否通过缺乏锌的 SOD 会使脊髓容易缺乏α-生育酚。我们的最终目标是表征硫辛酸是否可以改善α-生育酚缺乏的影响或降低毒性 SOD 对衰老大鼠的影响。我们提出的研究将为检验 CAM 如何提供机制基础可以协调抗氧化疗法来调节 ALS 的病程。