Synchronized Intestinal Electrical Stimulation for Obesity

描述（由申请人提供）： 在美国，肥胖及其并发症每年导致约40万人死亡，花费1400亿美元。在退伍军人患者中，肥胖症甚至更普遍，超过75%的患者超重或肥胖。然而，目前可用的疗法要么无效，要么具有显著的发病率和死亡率风险。 在这个项目中，我们提出了一种治疗肥胖症的肠道电刺激（IES）方法。初步数据表明IES对肥胖症具有治疗潜力，这归因于其对肠道运输的加速作用，导致吸收减少，以及其对外周和中枢激素/肽的作用，导致食物摄入减少。为了使IES治疗更有效和实用，我们进一步提出1）同步IES方法（SIES），其已被证明可改善肠道收缩，因此在加速肠道传输方面更有效; 2）自动食物摄入检测方法，通过该方法，IES/SIES可在食物摄入时自动递送。我们的长期目标是证明所提出的SIES/IES方法用于治疗肥胖的临床应用。本项目的主要目标是{优化IES方法，使其在不诱导副作用的情况下最有效地产生体重减轻，证明慢性IES/SIES的安全性和有效性，并探索涉及饮食诱导的肥胖（DIO）大鼠（一种成熟的人类肥胖啮齿动物模型）中胃肠动力和激素以及中枢饱腹感神经元和饱腹感/食欲相关肽的多种机制。} {The第一系列实验将在DIO大鼠中进行，以获得IES的最佳刺激参数和最佳刺激配置和最佳治疗方案。第二系列实验旨在证明慢性IES/SIES在DIO大鼠中产生体重减轻和改善代谢方面是安全有效的。本研究的第三部分是探讨IES对体重抑制作用的多种机制。实验旨在证明IES通过加速肠道运输减少营养吸收来减轻体重的主要假设。还将进行实验以研究与饱腹感信号传导相关的次级机制，包括胃肠激素、中枢神经元反应和中枢饱腹感/食欲相关肽。先进的技术将用于所有实验，使得IES治疗可以在正常生理条件下进行，没有或很少有应激效应。我们的团队在电刺激、胃肠动力、肥胖、外科手术、基础实验室研究和统计学方面都具有丰富的经验。本课题的完成将加深我们对IES的作用和机制的理解，并可能为肥胖症的治疗提供新的思路。

DESCRIPTION (provided by applicant): Obesity and its co-morbidities cause about 400,000 deaths and cost $140 billion per year in USA. In veteran patients, obesity is even more prevalent with over 75% of patients overweight or obese. However, currently available therapies are either ineffective or with significant risks o morbidities and mortality. In this project we propose a method of intestinal electrical stimulatio (IES) for treating obesity. Preliminary data have suggested a therapeutic potential of IES for obesity, attributed to its accelerative effect on intestinal transit that leads to reduced absorptin and its effects on peripheral and central hormones/peptides that lead to reduced food intake. To make the IES therapy more potent and practical, we further propose 1) a synchronized IES method (SIES) that has been shown to improve intestinal contractions and is therefore more potent in speeding up intestinal transit; 2) an automatic food intake detection method with which IES/SIES can be delivered automatically upon food ingestion. Our long-term goal is to prove the clinical application of the proposed SIES/IES method for treating obesity. The major objectives of this project are to {optimize IES methodology such that it is most potent in producing weight loss without inducing side-effects, to prove the safety and efficacy of chronic IES/SIES and to explore multiple mechanisms involving gastrointestinal motility and hormones, and central satiety neurons and satiety/appetite-related peptides in diet- induced obese (DIO) rats (a well-established rodent model of human obesity).} {The first series of experiments will be performed in DIO rats to derive best stimulation parameters for IES and best stimulation configuration and best treatment regimen. The second series of experiments are designed to prove that chronic IES/SIES is safe and effective in producing weight loss and improving metabolisms in DIO rats. The third part of the project is to explore multiple mechanisms involved in the inhibitory effect o IES on body weight. Experiments are designed to prove the primary hypothesis that IES reduces body weight by decreasing nutrient absorption via acceleration of intestinal transit. Experiments will also be performed to study the secondary mechanisms associated with satiety signaling, including gastrointestinal hormones, central neuronal responses and central satiety/appetite-related peptides. Advanced technologies will be used for all experiments such that the IES treatment could be given under normal physiological conditions with no or little stress effects. } A comprehensive and competitive team has been assembled with expertise in electrical stimulation, gastrointestinal motility, obesity, surgery, basic laboratory research and statistics. The accomplishment of this project will enhance our understanding on the effects and mechanisms of IES and may lead to a novel therapy for obesity.