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 儿科条件下生长抑素受体靶向的改进 巨人症是一种儿童发育障碍，导致生长激素水平异常高。 身高和腰围的过度增长。这种疾病可能会有严重的身体并发症，包括 糖尿病、失明以及社会孤立。在大多数情况下，巨人症是由脑下垂体引起的 腺瘤，当手术不能选择时，用生长抑素受体激动剂治疗以抑制 提高生长激素水平，缓解症状。生长抑素受体是G蛋白偶联的 受体(GPCRs)在垂体腺瘤中高表达。内源性多肽的两个类似物， 奥曲肽和兰瑞肽最初被开发为SSTR2选择性、长效多肽疗法，用于 巨人症和其他病症。虽然它们已被证明是成功的，但长期副作用和其他次优 房地产推动了对巨人症改进药物干预的需求。仍有许多未知之处 SSTR及其药理学。到目前为止，我已经确定了SSTR2的结构，但是一些问题 如果没有其他亚型的结构，亚型选择性仍未得到回答。大部分额外的 关于SSTR信令伙伴的信息是基于下游细胞分析的，而且还有很多 尚不清楚SSTR亚型选择性与信号伙伴偏向的相关性。在这里，我建议使用 结构表征与低温电子显微镜、分子动力学相结合 模拟和生化分析，以表征选择性、激活和信号特征 SSTR。这项工作将建立在我现有的分子模拟、建模和蛋白质方面的技能基础上 生物化学，同时在低温电子显微镜数据收集/处理和基于细胞的生化方面提供宝贵的培训 化验。这项工作的成功完成将使我们能够深入了解 生长抑素受体与配体和SSTR亚型G蛋白的结构基础 选择性。这将弥补在对SSTR的了解方面的几个差距，这些差距应该有助于制定改进的、 儿童不需要重复注射的小分子疗法。