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 改善生长抑素受体在儿科疾病中的靶向性 巨人症是一种儿童期发育障碍， 在身高和腰围上过度增长。这种疾病可能有严重的身体并发症，包括 糖尿病和视力丧失以及社会孤立。在大多数情况下，肥胖症是由垂体 腺瘤，当手术不是一种选择时，用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 GPCRs在垂体腺瘤中高表达。内源性肽的两种类似物， 奥曲肽和兰瑞肽最初是作为SSTR 2选择性、持久的肽治疗剂开发的， 抑郁症和其他病症。虽然他们已经证明是成功的，长期的副作用和其他次优 这些特性推动了对改善的药物干预的需求。还有很多未知的 SSTR及其药理学。到目前为止，我已经确定了SSTR 2的结构，但一些问题， 在没有其它子类型的结构的情况下，子类型选择性仍然没有得到回答。许多额外的 关于SSTR信号伴侣的信息是基于下游细胞分析， 关于SSTR亚型选择性和信号伴侣偏好的相关性未知。在这里，我建议利用一个 结合结构表征与低温电子显微镜（cryoEM），分子动力学 模拟和生物化学测定，以表征选择性，激活，和信号传导概况， SSTR。这项工作将建立在我在分子模拟、建模和蛋白质方面的现有技能基础上 同时提供cryoEM数据收集/处理和基于细胞的生化方面的宝贵培训 分析。这项工作的成功完成将提供关键的洞察信令景观的 生长抑素受体和基于配体和基于SSTR亚型的G蛋白的结构基础 选择性这将弥补在了解南南贸易战方面的一些空白， 小分子治疗剂，不需要在儿童中重复注射。