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.

项目总结

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

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

• DOI: 10.1016/j.molmet.2021.101422
• 发表时间: 2022-03
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Reiner BC;Crist RC;Borner T;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