Development of Ketone Ester Diets

酮酯饮食的开发

• 批准号: 6983087
• 负责人: richard l veech
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6983087
• 关键词: Rodentias; acidosis; biological models; biotherapeutic agent; butyrates; cognition; diet therapy; dietary supplements; drug design /synthesis /production; drug screening /evaluation; esters; ketone body; metabolism; microorganism mass culture; muscular dystrophy; nutrition related tag; therapy design /development

The Laboratory Chief has acted as principle investigator for a $3.8 million collaborative contract with DARPA to determine if a diet of ketone esters can enhance the metabolic and cognitive performance of war fighters under conditions of extreme physiological and emotional stress. The project involves: a) the production of esters of D-?O-hydroxybutyrate obtained the product of bacterial fermentation poly D-?O-hydroxybutyrate in collaboration with John Hammerstone of Mars Inc, b) determine the physiological and cognitive effects in collaboration with Prof. Kieran Clarke of Oxford University, c) test the ketone ester diet for toxicity in rodents and rodent newborns in collaboration with Prof. Carl Keen, UC Davis d) construct a non-invasive optical monitoring system to determine the level of ketosis in animals and man in collaboration with Prof Britton Chance, U of Pennsylvania e) determine, in the Laboratory of Metabolic Control, NIAAA, the levels and duration of ketosis achieved on feeding the ketone ester diet and the changes in intermediary and energy metabolites in heart and brain, and in collaboration with Drs George Kunos and Dr Douglas Osei-hyiaman of the Laboratory of Physiological Studies, NIAAA, changes in important neuropeptides that bear on changes in cognitive function during ketosis. f) model in silico, the metabolic changes that would occur during ketosis in collaboration with Dr. David Pollidori, Entelos Corporation. The projects outlined above are scheduled for completion by June, 2005. Assuming the goals of this project are met, then application will be made to DARPA for funds to formulate and test the effects of a ketone ester diet on the physiological and cognitive performance in military recruits undergoing different forms of extreme training exercises. The theoretical justification on which more efficient physiological performance during mild ketosis is anticipated have been described previously (1) where we showed that cardiac hydraulic efficiency could be increased by about 28%. The role of ketosis in overcoming insulin resistance, which accompanies extreme physical and psychological stress have also been described (2). Classically, ketosis has been induced by feeding high fat, low carbohydrate diets, however such diets can induce significant elevation in blood lipids with atherogenic potential (3). Alternative high fat diets have been proposed utilizing mid chain or unsaturated fatty acids (4;5), but are not well tolerated by patients. More importantly the feeding of high fat diets inevitably leads to the elevation of blood free fatty acids with consequent activation of the PPAR nuclear transcription system increasing the transcription of uncoupling proteins leading to metabolic inefficiency with decreased cardiac phosphorylation potential which can induce cardiac arrythmias and in some cases failure or unstable angina. The alternative to the feeding of a high fat diet is to create ketone esters which are hydrolysable by gut into ketone bodies. A ready and cheap source of poly D-?O-hydroxybutyrate is available as a fermentation product from Alcaligenes eutrophus (6). While the bacterial polymer in its native form is not digestible in gut, short esters are. The process to create such esters have involved new and novel means of production which are patentable. In addition to the military uses of such compounds, it appears that mild ketosis would be of therapeutic benefit in 3 major disease phenotypes: 1) diseases of substrate deficiency, such as Alzheimer's disease, types I & II diabetes, and insulin resistant states, 2) diseases of free radical toxicity, such as Parkinson's disease, amyotrophic lateral sclerosis and reperfusion injury and 3) disease of hypoxia, such as myocardial infarction and stroke. The medical uses of such compounds are also being investigated by Dr. Yoshihiro Kashiwaya, MD PhD in a visiting scientist in our laboratory. Duchenne?s and Becker?s muscular dystrophy is the most common monogenetic disease affecting 1/3,600 male births. The genetic lesion is a failure to synthesis dystrophin an structural muscle protein. Attempts to express dystrophin or eutrophin in these patients by molecular biological means have so far failed. Accordingly, there is no treatment for these patients with the result that they are wheelchair bound by the end of the first decade of life and die in the 2nd decade of either heart or respiratory failure. It has been found, by Prof Kieran Clarke and her collegues at Oxford University (25), that the mouse model of Duchenne?s , the mdx mouse, has impaired glucose uptake, possibly due to a decreased translocation of GLUT4 in response to insulin stimulation. This raises the possibility that these patients could be treated by inducing mild ketosis (2). We have therefore developed a system to measure the hydraulic efficiency in the working perfused mouse heart, a technique not accomplished by any other laboratory and one requiring considerable technical skill. We have now shown that the decreased hydraulic efficiency of working perfused MDX mouse hearts can be improved by addition of 5 mM Na D-?-hydroxybutyrate to the perfusion media. This raises the possibility of a potentially life saving form of therapy for these patients, for which no therapy now exists. During last year, and in collaboration with Dr. Roscoe Brady of NINDS we prepared applications in response to a DoD solicitation for new therapeutic approaches in the areas of 1) epilepsy, 2) Duchenne?s muscular dystrophy, and 3) amyotrophic lateral sclerosis. Unfortunately these applications were not successful and no funds were made available. However, I believe the approach outlines was sound, and if our present program of ester synthesis with DARPA is successful, these applications and the approach outlined should be submitted to NIH for further consideration. This material has been the subject of 2 meetings sponsored by the NIH Office of Rare Disease over the past 2 years. Dr Kashiwaya in collaboration with Dr. Ray Masuda, a Fogarty Fellow has also examined the effects of ketone bodies on hypoxia in cultured hippocampal neurons. A manuscript reporting the results of this work is in preparation. Significance to the Programs of the NIAAA Furtherance of defenses against bioterrorism is one of the priorities in the NIH roadmap and this collaboration with the Department of Defense is consonant with this NIH priority. The possibility of developing a new therapy for a presently untreatable diseases is of significance to the mission of the NIH and this institute.

这位实验室负责人是与DARPA的380万美元合作合同的主要研究人员，以确定酮酯饮食是否可以在极端的生理和情感压力的条件下增强战斗人员的代谢和认知表现。该项目涉及： a）D- o-羟基丁酸酯的产生获得了细菌发酵聚d- o-hydroxybutyrate的乘积，并与Mars Inc的John Hammerstone合作 b）与牛津大学的基兰·克拉克教授合作确定生理和认知效应， c）与加州大学戴维斯分校的卡尔·基恩（Carl Keen d）构建一个非侵入性光学监测系统，以确定动物和人与宾夕法尼亚州U教授合作的动物和人的酮症水平 e) determine, in the Laboratory of Metabolic Control, NIAAA, the levels and duration of ketosis achieved on feeding the ketone ester diet and the changes in intermediary and energy metabolites in heart and brain, and in collaboration with Drs George Kunos and Dr Douglas Osei-hyiaman of the Laboratory of Physiological Studies, NIAAA, changes in important neuropeptides that bear on changes in cognitive function during酮症。 f）模型在计算机中，与Entelos Corporation的David Pollidori博士合作，在酮症期间会发生代谢变化。 上面概述的项目计划在2005年6月之前完成。假设实现了该项目的目标，则将向DARPA提出申请，以供资金申请，以制定和测试酮酯饮食对经过不同形式的极端训练练习的军事招募人员在军事招募中的生理和认知表现的影响。先前已经描述了在轻度酮症中更有效的生理性能的理论理由（1），我们表明心脏液压效率可以提高约28％。酮症在克服胰岛素抵抗（伴随极端身体和心理压力）中的作用也已经描述了（2）。从经典上讲，酮症是通过喂养高脂肪，低碳水化合物饮食来诱导的，但是这种饮食可以诱导具有动脉粥样硬化潜力的血脂升高（3）。已经提出了使用中链或不饱和脂肪酸的替代高脂肪饮食（4; 5），但患者的耐受性不佳。更重要的是，高脂饮食不可避免地会导致无血液脂肪酸的升高，从而激活PPAR核转录系统，从而增加了解偶偶联蛋白的转录，从而导致代谢效率低下，而心脏磷酸化的潜力降低，从而诱导心脏弧菌和某些情况下的失败或不稳定的anginaa。 喂养高脂饮食的替代方法是创建酮酯，这些酮可以通过肠道水解为酮体。可从藻素的富集菌作为发酵产品可用的一种准备且廉价的聚二羟基丁酸酯来源（6）。尽管肠道中不可消化的细菌聚合物，但短酯是。创建此类酯的过程涉及可专利的新型生产手段。 In addition to the military uses of such compounds, it appears that mild ketosis would be of therapeutic benefit in 3 major disease phenotypes: 1) diseases of substrate deficiency, such as Alzheimer's disease, types I & II diabetes, and insulin resistant states, 2) diseases of free radical toxicity, such as Parkinson's disease, amyotrophic lateral sclerosis and reperfusion injury and 3) disease缺氧，例如心肌梗塞和中风。 此类化合物的医学用途也在我们实验室的一位客座科学家中，医学博士Yoshihiro Kashiwaya博士也正在研究。 Duchenne？s和Becker的肌肉营养不良是影响1/3,600个男性出生的最常见的单基因疾病。遗传病变是未能合成肌营养不良蛋白的结构肌肉蛋白。到目前为止，这些患者在这些患者中表达肌营养不良蛋白或富营养的尝试尚未失败。因此，对于这些患者没有治疗，其结果是他们的轮椅受生命的头十年结束，并且在心脏或呼吸衰竭的第二个十年中死亡。基兰·克拉克（Kieran Clarke）教授及其在牛津大学（25）的大学发现，MDX小鼠Duchenne的小鼠模型可能受损葡萄糖的摄取受损，这可能是由于GLUT4的易位减少而响应于胰岛素刺激。这增加了可以通过诱导轻度酮症治疗这些患者的可能性（2）。因此，我们已经开发了一个系统来测量工作灌注小鼠心脏的液压效率，这是任何其他实验室无法完成的技术，并且需要大量的技术技能。现在，我们已经表明，通过在灌注介质中添加5 mm Na D - ？ - 羟基丁酸，可以改善工作灌注MDX小鼠心脏的液压效率降低。这增加了为这些患者提供潜在的生命疗法形式的可能性，现在不存在治疗。 在去年，与Ninds的Roscoe Brady博士合作，我们为DOD征集了新的治疗方法的申请，以1）癫痫病，2）Duchenne？s肌肉营养不良，3）肌萎缩性侧面硬化症。不幸的是，这些应用程序没有成功，也没有提供资金。但是，我认为该方法的概述是正确的，如果我们目前与DARPA合成的酯合成计划是成功的，则这些应用程序以及概述的方法应提交NIH以进行进一步考虑。该材料是NIH稀有疾病办公室在过去两年中赞助的两次会议的主题。 Fogarty研究员雷·马苏达（Ray Masuda）博士在喀西亚亚博士（Kashiwaya）博士中还研究了酮体对培养的海马神经元中缺氧的影响。报告这项工作结果的手稿正在准备。 对NIAAA计划的意义 对抗生物恐怖主义的防御能力是NIH路线图的优先事项之一，与国防部的这种合作符合NIH的优先事项。为目前不可治疗的疾病开发新疗法的可能性对NIH和该研究所的使命具有重要意义。