Neural Mechanisms of Nausea, Vomiting, and Energy Dysregulation

项目摘要 恶心和呕吐促进了哺乳动物的生存。矛盾的是，呕吐的“副作用”无处不在。 报道了FDA批准的治疗肥胖、糖尿病和癌症的药物疗法和 与多种疾病并存，这些疾病会导致有害的危及生命的结果，如贫穷 营养、生活质量和患者预后。在这里，我们解决两个广泛的未得到满足的临床需求：1)所有现有的 FDA批准的基于GLP-1的治疗糖尿病和肥胖症的药物 有相当比例的患者会出现恶心和呕吐。2)尽管已有止吐治疗 几乎所有接受化疗的患者都会继续表现出严重的虚弱症状， 例如严重的恶心、呕吐和恶病质。我们使用现代行为和神经遗传学方法， 适当的、可比较的、临床前的动物模型，对于产生新的、有效的、长期的 控制恶心和呕吐以推进现代代谢性保健。肠道来源的GIP调节 餐后血糖通过直接作用于胰岛β细胞上表达的GIP受体(GIPR)。GIP 作为糖尿病和肥胖症的单一疗法，类似的疗效充其量是有限的，也是有争议的，然而， 中枢神经系统GIPRs在恶心/呕吐相关区域的表达引发了对中枢作用的研究 将GIP配体作为潜在的辅助治疗药物，以减少不良反应。具体来说，我们的数据 支持GIPR和GLP-1R双激动剂提供体重减轻、低吞噬和血糖调节控制 没有恶心和呕吐，与仅有GLP-1R激动剂相比，通过激活GIP系统。这一地区 迷走神经背侧复合体(DVC)的最后区(AP)和孤束核(NTS)在 吞咽行为、呕吐和恶心。广泛使用的催吐化疗药物(如顺铂)和所有FDA- 批准的基于GLP-1的配体激活AP/NTS神经元。我们的集体工作表明后脑GIPRS阻止了 GLP-1R和顺铂化疗引起的几种动物的恶心和呕吐，提示 GIPR激动剂的翻译广谱止吐潜力。我们已经确定了细胞表型 AP/NTS GIPR和GLP-1R表达细胞，AP/NTS神经元活性减弱； 初步数据)。此外，我们还发现了一个分子上不同的GABA能神经元DVC群体。 这是由化疗调节的，但被GIPR激动症所拯救。我们假设存在一种止吐剂 以表达GIP受体(GIPR)的抑制性(即GABA能)神经元为特征的系统。在这里，我们将： 目的I：研究GIPR-GABA AP/NTS的行为、解剖和转录机制 神经元表现出止吐作用。目标二：研究GIP止吐作用与已建立 使用多物种方法的止吐药物。我们在多个物种中的数据都表明GIP激动症具有 止吐作用，在这里，我们使用我们独特的多物种方法来定义GIP系统的机制 在减少和/或预防治疗性药物引起的恶心和呕吐方面。

Project Summary Nausea and vomiting promote mammalian survival. Paradoxically, emetic “side effects” are ubiquitously reported for FDA-approved pharmacotherapeutics for obesity, diabetes, and cancer pharmacotherapies and present alongside polymorbidities that contribute to detrimental life-threatening outcomes, such as poor nutrition, quality of life, and patient prognosis. Here, we address two broad unmet clinical needs: 1) All existing FDA-approved glucagon-like peptide-1 (GLP-1)-based therapeutics for the treatment of diabetes and obesity elicit nausea and vomiting in a significant percentage of patients. 2) Despite existing antiemetic treatments available, virtually all patients undergoing chemotherapy continue to exhibit profound debilitating symptoms, such as severe nausea, vomiting, and cachexia. We use modern behavioral and neurogenetic approaches, and appropriate, comparative, preclinical animal models that are critical to produce novel, effective, long-term controls of nausea and vomiting to advance modern metabolic health care. Intestinally derived GIP regulates postprandial glucose through direct action on GIP receptors (GIPR) expressed on pancreatic beta cells. GIP analog efficacy as a monotreatment of diabetes and obesity is at best limited and controversial, however, the expression of CNS GIPRs in regions implicated in nausea/emesis have spawned investigation of central actions of GIP ligands as potential adjunct therapeutics to reduce unwanted adverse events. Specifically, our data support that GIPR and GLP-1R dual agonism provide body weight loss, hypophagia, and glucoregulatory control without nausea and emesis, compared to GLP-1R agonism alone, through activation of the GIP system. The area postrema (AP) and nucleus tractus solitarius (NTS) of the dorsal vagal complex (DVC) play a critical role in ingestive behavior, emesis, and nausea. Widely used emetogenic chemotherapeutics (e.g., cisplatin) and all FDA- approved GLP-1-based ligands activate AP/NTS neurons. Our collective works suggest hindbrain GIPRs block nausea and vomiting induced by GLP-1R and cisplatin chemotherapy in several animal species, suggesting translational broad-spectrum antiemetic potential for GIPR agonists. We have identified cellular phenotypes of AP/NTS GIPR- and GLP-1R- expressing cells, as well as shown the attenuation in AP/NTS neuron activity, and preliminary data). Additionally, we have discovered a molecularly distinct GABA-ergic neuronal DVC population that is modulated by chemotherapy but rescued by GIPR agonism. We hypothesize that there exists an antiemetic system characterized by inhibitory (i.e., GABA-ergic) neurons expressing GIP receptors (GIPR). Here, we will: Aim I: Examine behavioral, anatomical, and transcriptomic mechanisms by which GIPR-GABA+ AP/NTS neurons exhibit antiemetic action. Aim II: Examine GIP antiemetic action in conjunction with established antiemetics using a multi-species approach. Our data in multiple species all indicate that GIP agonism has an antiemetic effect and here we use our unique multi-species approach to define the mechanisms of the GIP system in reducing and/or preventing therapeutic drug-induced nausea and emesis.