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.

概括生长分化因子 15 (GDF15)，以前称为巨噬细胞抑制性细胞因子-1 (MIC-1)，是一种细胞因子，在许多情况和疾病中表现出表达和血清升高，包括近年来，GDF15 信号传导在怀孕、肥胖、糖尿病和癌症等方面引起了广泛关注。 2017 年多篇论文鉴定 GDNF 家族受体 α 样 (GFRAL) 受体可结合 GDF15 然而，据报道，GFRAL 受体的限制性表达。脑干的后区 (AP) 和孤束核 (NTS)，这两个区域对于能量都非常关键平衡和呕吐/恶心/不适表明 GDF15-GFRAL 信号传导可能不仅是一个重要因素在长期体重调节中，也在短期处理呕吐和疾病行为中。了解 GDF15-GFRAL 信号在疾病行为和厌食症中发挥的作用至关重要确定 GDF15 作用机制的令人信服的证据将 GDF15 信号传导与化疗联系起来。引起恶心和厌食，尽管控制相对较好，但仍然是重要的临床问题化疗引起的呕吐，通过显示：1) GDF15 信号传导导致恶心和呕吐；2) AP/NTS；作用位点负责通过结合 GFRAL- 介导 GDF15 信号传导的喂养效应 RET 受体复合物，以及 3) 肥胖、癌症和化疗会增加啮齿动物和我们捕获了 NTS 中中央 GDF15 水平表达的功能动态变化。 AP 将在能量平衡失调和/或施用催吐刺激后发生，并且我们可以通过独特的分子和行为分析以及基于专利的肽来减轻/治疗这种情况这里采用的技术（即我们的基于肽的抑制剂绑定恶心新型 GFRAL-RET 拮抗剂“GRASP”）GRASP 拮抗剂是一种小型、序列与我们的体内和构象结合模型支持它是变构我们还证明 GRASP 可以渗透到脑干并 AP/NTS 中表达 GFRAL 的神经元，从而减弱 GDF15 和顺铂诱导的为了进一步探索 GDF15-GFRAL 系统，我们建议进行补充研究多 PI 团队由具有丰富协作经验的既定研究人员组成，可调查以下内容目标：目标我将表征内源性 GDF15 的脑干电路和无偏单细胞转录组学 Aim II 的产生和表达 GFRAL/RET 的神经元表型将表征 GDF15 诱导的呕吐，恶心行为和厌食症，以及针对这些行为的 GRASP 先导化合物的特征多物种方法将描述 GRASP 的关键机制和稳定性参数。通过基于功能、计算和结构数据的类似物的合理设计来构建我们的迄今为止成功的技术，旨在阻断 GFRAL 受体来治疗疾病，包括不必要的厌食、恶心和呕吐。