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.

项目摘要 恶心和呕吐促进哺乳动物的生存。矛盾的是，催眠的“副作用”普遍存在 报道了FDA批准的药物治疗药，用于肥胖，糖尿病和癌症药物疗法以及 与多种多样的伴随着有害生命的结果一样，例如差 营养，生活质量和患者提示。在这里，我们解决了两个广泛未满足的临床需求：1）所有现有 基于FDA批准的胰高血糖素样肽-1（GLP-1）的治疗剂，用于治疗糖尿病和肥胖症 在很大一部分患者中引起恶心和呕吐。 2）尽管现有抗过敏疗法 可用，几乎所有接受化疗的患者继续表现出严重的衰弱症状， 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，以及 适当，比较，临床前动物模型，对于产生新颖，有效，长期至关重要 恶心和呕吐的控制，以促进现代代谢保健。小肠派生的GIP调节 餐后葡萄糖通过在胰腺β细胞上表达的GIP受体（GIPR）的直接作用。 GIP 类似效率作为糖尿病和肥胖的单一治疗，充其量是有限的和有争议的，但是， CNS GIPR在恶心/发育中实施的地区的表达产生了中央动作的投资 GIP配体作为潜在的辅助疗法，以减少不需要的不良事件。具体来说，我们的数据 支持GIPR和GLP-1R双重激动剂可提供体重减轻，下降和葡萄糖调节控制 与单独的GLP-1R激动剂相比，通过激活GIP系统，没有恶心和呕吐。该区域 背面迷走神经配合物（DVC）的postrema（AP）和核曲纳斯特斯·纳特（NTS）在 摄取行为，呕吐和恶心。广泛使用的突出化学治疗剂（例如，顺铂）和所有FDA- 批准的基于GLP-1的配体激活AP/NTS神经元。我们的集体作品暗示了后脑GIPRS块 GLP-1R和顺铂化学疗法在几种动物物种中引起的恶心和呕吐，表明 GIPR激动剂的翻译宽光谱抗体潜力。我们已经确定了 AP/NTS GIPR-和GLP-1R表达细胞，并显示AP/NTS神经元活性的衰减以及 初步数据）。此外，我们发现了一个分子不同的GABA - 凝胶神经元DVC种群 这是由化学疗法调节，但被GIPR激动剂挽救了。我们假设存在一种反女性 以抑制性（即GABA - 凝胶）神经元表达GIP受体（GIPR）为特征的系统。在这里，我们将： 目的I：检查GIPR-GABA+ AP/NTS的行为，解剖和转录机制 神经元暴露了抗过敏作用。 AIM II：与已建立的GIP抗过敏作用检查 使用多种物种方法的抗单位。我们在多种物种中的数据都表明GIP激动剂具有 抗气效应，在这里我们使用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。

项目成果

Creation of a Peptide Antagonist of the GFRAL-RET Receptor Complex for the Treatment of GDF15-Induced Malaise.

• DOI: 10.1021/acs.jmedchem.3c00667
• 发表时间: 2023-08-24
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Borner, Tito;Tinsley, Ian C. C.;Milliken, Brandon T. T.;Doebley, Sarah A. A.;Najjar, Nicholas R. R.;Kerwood, Deborah J. J.;De Jonghe, Bart C. C.;Hayes, Matthew R. R.;Doyle, Robert P. P.
• 通讯作者: Doyle, Robert P. P.

Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while CNS entry is required for locomotor and taste avoidance effects.

• DOI: 10.1111/dom.14937
• 发表时间: 2023-03
• 期刊: Diabetes, obesity & metabolism

Glucagon-like peptide-1 in diabetes care: Can glycaemic control be achieved without nausea and vomiting?

• DOI: 10.1111/bph.15647
• 发表时间: 2022-03
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Borner T;Tinsley IC;Doyle RP;Hayes MR;De Jonghe BC
• 通讯作者: De Jonghe BC

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

• DOI: 10.2337/db21-0459
• 发表时间: 2021-11
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Borner T;Geisler CE;Fortin SM;Cosgrove R;Alsina-Fernandez J;Dogra M;Doebley S;Sanchez-Navarro MJ;Leon RM;Gaisinsky J;White A;Bamezai A;Ghidewon MY;Grill HJ;Crist RC;Reiner BC;Ai M;Samms RJ;De Jonghe BC;Hayes MR
• 通讯作者: Hayes MR

Myocardial apoptosis and mesenchymal stem cells with acute exercise.

• DOI: 10.14814/phy2.13297
• 发表时间: 2017-06
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Arisi MF;Chirico EN;Sebeny R;Muthukumaran G;Mu A;De Jonghe BC;Margulies KB;Libonati JR
• 通讯作者: Libonati JR