Improved Targeting of Somatostatin Receptors for Pediatric Conditions
改善儿科疾病生长抑素受体的靶向性
基本信息
- 批准号:10525773
- 负责人:
- 金额:$ 12.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AgonistAntineoplastic AgentsArrestinsBehaviorBindingBiochemicalBiological AssayBioluminescenceBlindnessCell LineCellsCellular AssayChildChildhoodComplexDataData CollectionDevelopmentDiabetes MellitusDiseaseElectron MicroscopyEnergy TransferExhibitsFDA approvedFamily memberFree EnergyG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGigantismGoalsGrowthHeightInjectionsInsulinInterventionKnowledgeLigandsModelingMolecularMolecular ConformationMolecular WeightNeuroendocrine TumorsNeurosecretory SystemsOctreotideOperative Surgical ProceduresOralPeptidesPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePharmacologyPituitary GlandPituitary Gland AdenomaProductionPropertyProtein BiochemistryReceptor ActivationReceptor SignalingResolutionRunningSSTR1 geneSSTR2 geneSSTR3 geneSignal TransductionSocial isolationSomatostatinSomatostatin ReceptorSomatotrophin increasedSomatotropinStructureSymptomsTestingTherapeuticTherapeutic EffectTrainingTransmembrane DomainWorkanalogantagonistbaseclinically relevantcostcryogenicsdesigndevelopmental diseasedifferential expressiondrug developmentimprovedinsightmolecular dynamicsnanobodiesnext generationpeptide analogpeptide drugreceptorreceptor couplingrecruitreduce symptomsside effectsimulationsmall moleculesmall molecule therapeuticssocialsuccesssymptom treatment
项目摘要
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
测定。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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael Robertson其他文献
Michael Robertson的其他文献
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{{ truncateString('Michael Robertson', 18)}}的其他基金
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:
10687916 - 财政年份:2022
- 资助金额:
$ 12.2万 - 项目类别:
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