Improved Targeting of Somatostatin Receptors for Pediatric Conditions

改善儿科疾病生长抑素受体的靶向性

• 批准号: 10525773
• 负责人: Michael Robertson
• 金额: $ 12.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525773
• 关键词: Agonist; Antineoplastic Agents; Arrestins; Behavior; Binding; Biochemical; Biological Assay; Bioluminescence; Blindness; Cell Line; Cells; Cellular Assay; Child; Childhood; Complex; Data; Data Collection; Development; Diabetes Mellitus; Disease; Electron Microscopy; Energy Transfer; Exhibits; FDA approved; Family member; Free Energy; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gigantism; Goals; Growth; Height; Injections; Insulin; Intervention; Knowledge; Ligands; Modeling; Molecular; Molecular Conformation; Molecular Weight; Neuroendocrine Tumors; Neurosecretory Systems; Octreotide; Operative Surgical Procedures; Oral; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pituitary Gland; Pituitary Gland Adenoma; Production; Property; Protein Biochemistry; Receptor Activation; Receptor Signaling; Resolution; Running; SSTR1 gene; SSTR2 gene; SSTR3 gene; Signal Transduction; Social isolation; Somatostatin; Somatostatin Receptor; Somatotrophin increased; Somatotropin; Structure; Symptoms; Testing; Therapeutic; Therapeutic Effect; Training; Transmembrane Domain; Work; analog; antagonist; base; clinically relevant; cost; cryogenics; design; developmental disease; differential expression; drug development; improved; insight; molecular dynamics; nanobodies; next generation; peptide analog; peptide drug; receptor; receptor coupling; recruit; reduce symptoms; side effect; simulation; small molecule; small molecule therapeutics; social; success; symptom treatment

PROJECT ABSTRACT Improved Targeting of Somatostatin Receptors for Pediatric Conditions Gigantism is a childhood developmental disorder whereby abnormally high levels of growth hormone result in excessive growth in both height and girth. The disorder can have serious physical complications including diabetes and loss of vision as well as social isolation. In the majority of cases gigantism is caused by pituitary adenomas which, when surgery is not an option, is treated with somatostatin receptor agonists to suppress growth hormone levels and provide symptom relief. Somatostatin receptors (SSTRs) are G protein coupled receptors (GPCRs) highly expressed in pituitary adenomas. Two analogues of the endogenous peptide, octreotide and lanreotide, were originally developed as SSTR2-selective, long-lasting peptide therapeutics for gigantism and other conditions. While they have proved successful, long-term side effects and other suboptimal properties drive the need for improved pharmaceutical interventions for gigantism. Much remains unknown about SSTRs and their pharmacology. To date, I have determined structures of SSTR2, however some questions of subtype selectivity remain unanswered without structures of the other subtypes. Much of the additional information about SSTR signaling partners is based upon downstream cellular assays, and much remains unknown about the relevance of SSTR subtype selectivity and signaling partner bias. Here I propose to utilize a combination of structural characterization with cryogenic electron microscopy (cryoEM), molecular dynamics simulations, and biochemical assays in order to characterize the selectivity, activation, and signaling profiles of SSTRs. The work will build upon my existing skillset in molecular simulations, modelling, and protein biochemistry while providing invaluable training in cryoEM data collection/processing and cell-based biochemical assays. Successful completion of this work will provide critical insight into the signaling landscape of the somatostatin receptor and the structural basis for both ligand-based and SSTR-subtype-based G protein selectivity. This will bridge several gaps in knowledge of SSTRs that should help in the development of improved, small molecule therapeutics that do not require repeated injections in children.

项目摘要 改善了生长抑素受体针对小儿疾病的靶向 巨人主义是一种童年发育障碍 高度和周长的过度生长。该疾病可能患有严重的身体并发症，包括 糖尿病和视力丧失以及社会隔离。在大多数情况下，巨大主义是由垂体引起的 腺瘤，当无法选择手术时，会接受生长抑素受体激动剂治疗以抑制 生长激素水平并提供症状缓解。生长抑素受体（SSTR）是G蛋白偶联的 在垂体腺瘤中高度表达的受体（GPCR）。内源性肽的两个类似物， 奥曲肽和腺苷最初是作为SSTR2选择性的，持久的肽疗法开发的 巨大主义和其他条件。尽管事实证明他们成功了，但长期副作用和其他次优的 属性推动了对巨人主义的改进药物干预措施的需求。关于 SSTR及其药理学。迄今为止，我已经确定了SSTR2的结构，但是有些问题 亚型的选择性在没有其他亚型结构的情况下保持不变。大部分附加 有关SSTR信号合作伙伴的信息是基于下游蜂窝测定的，并且仍然存在很多保留 关于SSTR子类型选择性和信号伴侣偏差的相关性未知。在这里，我建议利用一个 结构表征与低温电子显微镜（冷冻），分子动力学的组合 模拟和生化测定，以表征选择性，激活和信号传导曲线 SSTR。这项工作将基于我现有的分子模拟，建模和蛋白质的技能。 生物化学在冷冻数据收集/处理和基于细胞的生化的过程中提供宝贵的培训 测定。成功完成这项工作将为您的信号景观提供重要的见解 基于配体和基于SSTR-SUBTYPE的G蛋白的生长抑素受体和结构基础 选择性。这将弥合SSTR知识的几个差距，这应该有助于发展改进， 不需要对儿童重复注射的小分子疗法。