Targeting the GDF15-GFRAL system to treat nausea and emesis

总结 生长分化因子15（GDF 15），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，其在响应许多病症和疾病时显示表达和血清升高，包括 怀孕肥胖糖尿病和癌症近年来，GDF 15信号传导获得了显著的关注， 2017年的多篇论文将GDNF家族受体α样（GFRAL）受体鉴定为结合GDF 15 选择性和高亲和力。然而，所报道的GFRAL受体限制性表达于 脑干的最后区（AP）和孤束核（NTS），这些区域对这两种能量都非常关键 平衡和呕吐/恶心/不适表明GDF 15-GFRAL信号传导不仅是一个重要因素， 在长期的体重调节，而且在短期的呕吐和疾病的处理。行为因此，在本发明中， 了解GDF 15-GFRAL信号在疾病行为和厌食症中的作用至关重要， 确定GDF 15作用的机制。令人信服的证据将GDF 15信号传导与化疗联系起来- 引起的恶心和厌食，尽管控制相对良好，但仍然是重要的临床问题 通过显示：1）GDF 15信号传导引起恶心和呕吐; 2）AP/NTS 作用位点负责介导GDF 15信号传导的摄食作用，通过GFRAL-1的结合。 RET受体复合物，和3）肥胖，癌症和化疗增加啮齿类动物中的循环GDF 15， 人类我们假设NTS中枢GDF 15表达水平的功能性动态变化可能与NTS中GDF 15表达水平的变化有关。 和AP将在能量平衡失调和/或给予催吐刺激后发生， 可以通过独特的分子和行为分析以及基于专利肽的 技术（即我们的 基于肽 抑制剂 结合 恶心 新GFRAL-RET拮抗剂“GRASP”）。GRASP拮抗剂是一种小， 序列与我们的体内和构象结合模型支持它是一个变构 GFRAL-RET复合体我们还表明，GRASP可以渗透到脑干， AP/NTS中表达GFRAL的神经元，从而减弱GDF 15和顺铂诱导的 为了进一步探索GDF 15-GFRAL系统，我们提出了一个免费的研究， 由具有丰富合作经验的资深研究者组成的多PI团队，以研究以下内容 目的：目的我将表征脑干回路和无偏倚的单细胞转录组学内源性GDF 15 产生和表达GFRAL/RET的神经元表型。目的II将表征GDF 15诱导的呕吐， 恶心行为和厌食症，并以 多物种方法。目标三将描述大型类人猿生存项目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， 迄今为止，成功的技术试图阻断GFRAL受体来治疗疾病，包括 不必要的厌食恶心和呕吐

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.