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Targeting the GDF15-GFRAL system to treat nausea and emesis

靶向 GDF15-GFRAL 系统治疗恶心和呕吐

基本信息

批准号：
10630836
负责人：
Bart C DE JONGHE
金额：
$ 67.01万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630836
关键词：
3-Dimensional Ablation Affinity Anorexia Antibodies Antiemetics Appetite Depressants Area Attention Attenuated Base Sequence Behavior Behavioral Behavioral Assay Binding Biological Assay Body Weight Body Weight decreased Brain Stem Cachexia Cell Nucleus Cells Cellular Metabolic Process Chronic Chronic Disease Circulation Cisplatin Clinical Complex Data Development Diabetes Mellitus Disease Distress Drug Kinetics Emetics Endothelium Equilibrium Family Feeding behaviors Fluorescent in Situ Hybridization GDF15 gene Generations Goals Health Human Hunger In Vitro Knockout Mice Lead Legal patent Lesion Link Literature Malaise Malignant Neoplasms Measures Mediating Mediator Medicine Metabolic Diseases Microglia Modeling Molecular Molecular Conformation Mus Nausea Nausea and Vomiting Neurobiology Neurons Obesity Output Pain Paper Pathologic Penetration Peptides Peripheral Pharmacodynamics Pharmacotherapy Phenotype Plasma Play Pregnancy Process Production Publishing Rattus Regulation Reporting Research Personnel Rodent Role Science Serum Shrews Sick Role Signal Transduction Site Stimulus Stress Structure Structure of area postrema Syndrome System Technology Testing Tissues Vomiting Weight Gain analog antagonist behavioral pharmacology cancer anorexia cancer therapy chemotherapy cytokine energy balance experience feeding genomic platform glial cell-line derived neurotrophic factor improved in vivo in vivo evaluation inhibitor neural novel obesity treatment rational design receptor response trafficking transcriptome transcriptomics

项目摘要

Summary The growth differentiation factor 15 (GDF15), formerly known as macrophage inhibitory cytokine-1 (MIC-1), is a cytokine that shows expression and serum rise in response to many conditions and diseases, including pregnancy, obesity, diabetes, and cancer. GDF15 signaling has gained significant attention in recent years with multiple papers in 2017 identifying the GDNF family receptor α-like ( GFRAL ) receptor as binding GDF15 selectivelyand with high affinity. However, the reported restrictive expression of the GFRAL receptor to the area postrema (AP) and nucleus tractus solitarius (NTS) of the brainstem, areas highly critical to both energy balance and emesis/nausea/malaise suggests that GDF15-GFRAL signaling could be an important factor not only in long-term body weight regulation, but also in short-term processing of emesis and illness. Behavior. Thus, understanding what role GDF15-GFRAL signaling plays in illness behavior and anorexia is paramount to determining the mechanism of GDF15 action. Compelling evidence links GDF15 signaling with chemotherapy- induced nausea and anorexia, which remain important clinical problems despite relatively well-controlled chemotherapy-induced emesis, by showing that: 1) GDF15 signaling causes nausea and emesis; 2) an AP/NTS site of action is responsible for mediating the feeding effects of GDF15 signaling through binding of the GFRAL- RET receptor complex, and 3) obesity, cancer, and chemotherapy increase circulating GDF15 in rodents and humans. We hypothesize that a functional dynamic change in the expression of central GDF15 levels in the NTS and AP will occur following energy balance dysregulation and/or administration of emetic stimuli, and that we can mitigate/treat such through the unique molecular and behavioral assays and patented peptide-based technology employed here (i.e. our peptide-based inhibitor bind nausea novel GFRAL-RET antagonist “GRASP”). The GRASP antagonist is a small, sequence with our in vivo and conformational binding models supporting it to be an allosteric to the GFRAL-RET complex. We have also shown that GRASP can penetrate into the brainstem and to GFRAL-expressing neurons in the AP/NTS, and consequently attenuate GDF15- and cisplatin-induced behaviors in rats.To further explore the GDF15-GFRAL system, we propose complimentary studies by a multi-PI team of established investigators with extensive collaborative experience to investigate the following aims: Aim I will characterize brainstem circuitry and unbiased single cell transcriptomics for endogenous GDF15 production and GFRAL/RET-expressing neuronal phenotypes. Aim II will characterize GDF15-induced emesis, nausea behavior, and anorexia as well as characterize the GRASP lead compound against these behaviors with a multi-species approach. Aim III will characterize the critical mechanistic and stability parameters of GRASP through rational design of analogs based on functional, computational and structural data to build upon our successful technology to-date that seeks to block the GFRAL receptor to treat sickness measures that include unwanted anorexia, nausea and emesis.

总结