Neural Mechanisms of Nausea, Vomiting, and Energy Dysregulation

恶心、呕吐和能量失调的神经机制

• 批准号: 10752271
• 负责人: Bart C DE JONGHE
• 金额: $ 63.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752271
• 关键词: Address; Adverse event; Agonist; Anatomy; Animal Model; Animals; Antiemetic Effect; Antiemetics; Attenuated; Award; Behavior; Behavioral; Body Weight decreased; Cachexia; Cell Nucleus; Cells; Chronic; Chronic Disease; Cisplatin; Clinical; Clinical Trials; Complex; Data; Diabetes Mellitus; Dorsal; Drug Side Effects; Emetics; Ensure; Exhibits; FDA approved; Feeding behaviors; Ferrets; GABA Receptor; Gastric Inhibitory Polypeptide; Genetic Transcription; Glucose; Healthcare; Heterogeneity; Intestines; Investigation; Life; Ligands; Malaise; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolic Diseases; Modernization; Molecular; Mus; Nausea; Nausea and Vomiting; Nausea and Vomiting Therapy; Neuroanatomy; Neurons; Neurosecretory Systems; Obesity; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiology; Play; Population; Pre-Clinical Model; Publications; Publishing; Quality of life; Rattus; Receptor Activation; Receptor Signaling; Reporting; Role; Shrews; Stimulus; Structure of area postrema; Structure of beta Cell of islet; System; TACR1 gene; Testing; Therapeutic; Vomiting; Work; analog; antagonist; attenuation; behavioral pharmacology; chemotherapy; clinically relevant; comorbidity; comparative; disabling symptom; gastric inhibitory polypeptide receptor; gastrointestinal; glucagon-like peptide 1; glycemic control; hindbrain; improved; neural; neurogenetics; neuromechanism; novel; nutrition; patient prognosis; pre-clinical; prevent; response; side effect; transcriptomics; virtual

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.

项目概要 恶心和呕吐促进哺乳动物的生存，但矛盾的是，呕吐的“副作用”却无处不在。 报告 FDA 批准的治疗肥胖、糖尿病和癌症的药物疗法，以及 与多种疾病同时存在，会导致有害的危及生命的结果，例如贫困 在这里，我们解决两个广泛的未满足的临床需求：1) 所有现有的。 FDA 批准的基于胰高血糖素样肽 1 (GLP-1) 的疗法用于治疗糖尿病和肥胖症 2) 尽管有现有的止吐治疗，但仍引起相当大比例的患者恶心和呕吐。 事实上，几乎所有接受化疗的患者都继续表现出严重的衰弱症状， 例如严重恶心、呕吐和恶病质，我们使用现代行为和神经遗传学方法，以及 适当的、比较性的临床前动物模型对于产生新颖、有效、长期的至关重要 控制恶心和呕吐以促进现代代谢保健。 通过直接作用于胰腺 β 细胞上表达的 GIP 受体 (GIPR) 来调节餐后血糖。 作为糖尿病和肥胖症的单一治疗方法，类似物的疗效至多是有限的且有争议的，然而， 中枢神经系统 GIPR 在与恶心/呕吐有关的区域中的表达引发了对中枢作用的研究 GIP 配体作为潜在的辅助疗法可以减少不必要的不​​良事件。具体来说，我们的数据。 支持 GIPR 和 GLP-1R 双重激动作用可实现体重减轻、吞咽功能减退和血糖调节控制 通过激活 GIP 系统，与单独使用 GLP-1R 激动剂相比，没有恶心和呕吐。 背侧迷走神经复合体 (DVC) 的后部 (AP) 和孤束核 (NTS) 在 摄入行为、呕吐和恶心。广泛使用的致吐化疗药物（例如顺铂）和所有 FDA 批准的药物。 经批准的基于 GLP-1 的配体可激活 AP/NTS 神经元，我们的集体工作表明后脑 GIPR 阻断。 GLP-1R 和顺铂化疗在多种动物中引起恶心和呕吐，表明 GIPR 激动剂的转化广谱止吐潜力我们已经确定了 GIPR 激动剂的细胞表型。 AP/NTS GIPR 和 GLP-1R 表达细胞，并显示 AP/NTS 神经元活性减弱，以及 此外，我们还发现了分子上不同的 GABA 能神经 DVC 群体 这是通过化疗调节但通过 GIPR 激动剂来拯救的。我们努力寻找止吐药的存在。 系统的特征是表达 GIP 受体 (GIPR) 的抑制性（即 GABA 能）神经元。 目标 I：检查 GIPR-GABA+ AP/NTS 的行为、解剖和转录组机制 目标 II：结合已确定的 GIP 止吐作用。 我们在多个物种中的数据均表明 GIP 激动具有一定的作用。 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 减少和/或预防治疗药物引起的恶心和呕吐。

项目成果

Activation of PPG neurons following acute stressors differentially involves hindbrain serotonin in male rats.

雄性大鼠急性应激源后 PPG 神经元的激活差异涉及后脑血清素。

• 发表时间: 2021
• 影响因子: 4.7
• 作者: Leon, Rosa M;Borner, Tito;Stein, Lauren M;Urrutia, Norma A;De Jonghe, Bart C;Schmidt, Heath D;Hayes, Matthew R
• 通讯作者: Hayes, Matthew R

Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment.

GDF15 处理后大鼠 AP 和 NTS 的单核 RNA 测序。

• 发表时间: 2022-02
• 影响因子: 8.1
• 作者: Reiner, Benjamin C;Crist, Richard C;Borner, Tito;Doyle, Robert P;Hayes, Matthew R;De Jonghe, Bart C
• 通讯作者: De Jonghe, Bart C

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.

GIP 受体激动可减轻临床前模型中 GLP-1 受体激动剂引起的恶心和呕吐。

• 发表时间: 2021-11
• 影响因子: 7.7
• 作者: Borner, Tito;Geisler, Caroline E;Fortin, Samantha M;Cosgrove, Richard;Alsina;Dogra, Mridula;Doebley, Sarah;Sanchez;Leon, Rosa M;Gaisinsky, Jane;White, Arianna;Bamezai, Ankur;Ghidewon, Misgana Y;Grill, Harvey
• 通讯作者: Grill, Harvey

Hypophagia induced by salmon calcitonin, but not by amylin, is partially driven by malaise and is mediated by CGRP neurons.

由鲑鱼降钙素（而非胰淀素）引起的吞咽不足部分是由不适引起的，并由 CGRP 神经元介导。

• 发表时间: 2022-04
• 影响因子: 8.1
• 作者: Boccia, Lavinia;Borner, Tito;Ghidewon, Misgana Y;Kulka, Patricia;Piffaretti, Chiara;Doebley, Sarah A;De Jonghe, Bart C;Grill, Harvey J;Lutz, Thomas A;Le Foll, Christelle
• 通讯作者: Le Foll, Christelle

A Neural Circuit for the Suppression of Pain by a Competing Need State.

通过竞争性需求状态抑制疼痛的神经回路。

• 发表时间: 2018
• 影响因子: 64.5
• 作者: Alhadeff, Amber L;Su, Zhenwei;Hernandez, Elen;Klima, Michelle L;Phillips, Sophie Z;Holland, Ruby A;Guo, Caiying;Hantman, Adam W;De Jonghe, Bart C;Betley, J Nicholas
• 通讯作者: Betley, J Nicholas