New Concepts for Advancing Knowledge in Basic Science, Clinical, and Therapeutic Aspects of Gastroparesis

摘要： 胃轻瘫(GP)以慢性上消化道动力障碍症状为主要表现。 胃排空无任何机械性梗阻。主观与主观之间存在不一致 GP的症状严重程度和客观证据以及可用的治疗方法受到以下方面的限制 不良事件和不可预测的疗效。因此，病理生理学、临床病程、结果和 治疗策略需要进一步研究。我们对NIDDK胃瘫的反应 RFA-DK-16-010下的联合体(U01)有以下目标： 1)完成由GpCRC发起的经批准的研究，该研究需要招募全科医生患者参加 胃轻瘫登记表2及其临床资料和生物标本以及获取胃组织 根据胃轻瘫(PBG)的病理基础，当一些患者接受手术时 因为失败的药物治疗。这种数据收集将有助于更多关于发病机制的知识， 慢性阻塞性肺疾病患者的病理形态、症状严重程度分级、并发症和治疗结果 GP和胃轻瘫样表现，但胃排空正常。 2)作为一种新的诊断策略，我们建议确定内窥镜超声(EUS)是否- GP患者胃窦固有肌核心活检标本可提供足够的组织 进行全面的组织学分析，以明确Cajal肌间神经丛间质细胞的状态 神经元和平滑肌病理学。在再次确认了这个项目的安全性和成功之后 一项对30例同时接受内窥镜和手术活检的患者的方法学研究 进入GpR3和GpR2登记将接受EUS引导下的胃窦核心活检 固有肌群作为数据库的一部分。因此我们将调查内窥镜检查是否 该方法可以安全地取代手术获取平滑肌组织，并将ICC的结果与 症状、胃排空和治疗结果。 3)我们建议研究一种新的多巴胺D2/D3拮抗剂的治疗效果。 对糖尿病或特发性胃轻瘫患者进行多中心、双重检查 盲法、随机、安慰剂对照、平行三组研究，也将评估心脏 安全性和不良事件。NIH的计划是与两家制药公司中的一家合作 公司正在开发新的药物，多巴胺D2/D3拮抗剂，没有心脏毒性。所有GpR3 患者将被邀请参加两个平行的12周糖尿病和特发性糖尿病病因试验。 胃瘫。 如果我们获得这笔赠款，TTU研究团队将致力于促进 并在GpCRC和NIDDK/NIH的监督下与其他中心合作。

Abstract: Gastroparesis (GP) presents with chronic upper GI dysmotility symptoms in the setting of delayed gastric emptying without any mechanical obstruction. Inconsistencies exist between subjective symptom severity and objective evidence of GP, and available therapies are limited by accompanying adverse events and unpredictable efficacy. Hence the pathophysiology, clinical course, outcomes and treatment strategies require further investigation. Our response to the NIDDK Gastroparesis Consortium (U01) under RFA-DK-16-010 has the following aims: 1) To complete approved studies initiated by the GpCRC which entails enrolling GP patients to Gastroparesis Registry 2 with their clinical data and bio-samples as well as obtain gastric tissue under the pathological basis of gastroparesis (PBG) protocol, when some patients undergo surgery for failed medical therapy. This data collection will contribute more knowledge about pathogenesis, pathomorphology, symptoms severity grading, complications, treatment outcomes in patients with GP and gastroparesis-like presentation but normal gastric emptying. 2) As a new diagnostic strategy, we propose to determine whether endoscopic ultrasound (EUS)- guided core biopsy samples of antral muscularis propria in GP patients can provide sufficient tissue for full histologic analysis to specifically address status of interstitial cell of Cajal, myenteric plexus neurons and smooth muscle pathology. After reconfirming the safety and success of this methodology in a study of 30 patients receiving both endoscopic and surgical biopsies all patients entering GpR3 as well as GpR2 registry will undergo EUS guided core biopsies of the antral muscularis propria as part of the database. Therefore we will investigate whether this endoscopic method can safely replace surgery to obtain smooth muscle tissue and correlate ICC findings with symptoms, gastric emptying and treatment outcome. 3) We propose to investigate the therapeutic efficacy of a new Dopamine D2/D3 antagonist in gastroparetic patients of either diabetic or idiopathic etiology by performing a multicenter, double- blind, randomized, placebo-controlled, parallel three-group study which will also assess cardiac safety and adverse event. The plan is for the NIH to partner with one of the 2 pharmaceutical companies developing new agents, Dopamine D2/D3 antagonists with no cardiac toxicity. All GpR3 patients will be invited to enroll into 2 parallel 12 week trials for diabetic and idiopathic etiologies of gastroparesis. If we are awarded this grant, TTU research team is committed to facilitate the execution of the protocols and collaborate with other Centers under GpCRC and NIDDK/NIH supervision.