Targeting the GDF15-GFRAL system to treat nausea and emesis

靶向 GDF15-GFRAL 系统治疗恶心和呕吐

• 批准号: 10463832
• 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
• 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/10463832
• 关键词: 3-Dimensional; Ablation; Affinity; Anorexia; Antibodies; Antiemetics; Appetite Depressants; Area; Attention; Attenuated; Base Sequence; Behavior; Behavioral; Behavioral Assay; Binding; Biological Assay; Blood Circulation; Body Weight; Body Weight decreased; Brain Stem; Cachexia; Cell Nucleus; Cells; Cellular Metabolic Process; Chemotherapy-Oncologic Procedure; Chronic; Chronic Disease; 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 of activation protein; Medicine; Metabolic Diseases; Microglia; Modeling; Molecular; Molecular Conformation; Mus; Nausea; Nausea and Vomiting; Neurobiology; Neurons; Obesity; Output; Pain; Paper; Pathologic; 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; base; behavioral pharmacology; cancer anorexia; chemotherapy; cytokine; energy balance; experience; feeding; genomic platform; glial cell-line derived neurotrophic factor; improved; in vivo; in vivo evaluation; inhibitor; novel; obesity treatment; rational design; receptor; relating to nervous system; response; trafficking; transcriptome; transcriptomics

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，显示出对许多疾病和疾病的反应，包括 怀孕，肥胖，糖尿病和癌症。近年来，GDF15信号引起了人们的关注 2017年的多篇论文确定GDNF家族受体α样（GFRAL）受体是结合GDF15 有选择地和高亲和力。但是，报道的GFRAL接收器对 脑干的区域postrema（AP）和核曲纳特斯·纳特（NTS） 平衡和呕吐/恶心/不适表明GDF15-GFRAL信号不仅是一个重要因素 在长期体重调节中，以及在短期处理呕吐和疾病中。行为。那， 了解GDF15-GFRAL信号在疾病行为和厌食症中的作用至关重要 确定GDF15动作的机制。令人信服的证据将GDF15信号与化学疗法联系起来 - 诱发的恶心和厌食症，尽管相对良好控制，但仍然是重要的临床问题 化学疗法诱导的呕吐，证明：1）GDF15信号传导会引起恶心和屈服； 2）AP/NTS 作用部位负责通过GFRAL-的结合来介导GDF15信号传导的进食效应 RET受体复合物以及3）肥胖，癌症和化学疗法增加啮齿动物的循环GDF15和 人类。我们假设NTS中心GDF15水平的表达功能动态变化 在能量平衡失调和/或给予催吐刺激的情况下，AP将发生，我们 可以通过独特的分子和行为测定以及基于专利的肽来减轻/治疗 在这里进行的技术（即我们的 基于肽的 抑制剂 绑定 恶心 新颖的GFRAL-RET拮抗剂“ Grasp”）。抓住的拮抗剂是一个小的 与我们的体内和构象结合模型的序列，支持它为变构 到GFRAL-RET综合体。我们还表明，掌握可以渗透到脑干中，并且 在AP/NTS中表达GFRAL的神经元，因此衰减了GDF15-和顺铂诱导的 大鼠行为。为了进一步探索GDF15-GFRAL系统，我们提出了通过 拥有丰富协作经验的成立研究人员的多PI-PI团队可以调查以下 目的：目标我将表征内源性GDF15的脑干电路和无偏见的单细胞转录组学 生产和GFRAL/表达神经元表型。 AIM II将表征GDF15诱导的ESES， 恶心的行为和厌食症，并表征了与这些行为相对于这些行为的掌握铅化合物 多物种方法。 AIM III将表征关键的机械和稳定性参数 通过基于功能，计算和结构数据的合理设计，以基于我们 旨在阻止GFRAL受体以治疗疾病措施的成功技术至今 不必要的厌食症，恶心和呕吐。