Identification and characterization of receptors targeting VGF-derived peptides.

针对 VGF 衍生肽的受体的鉴定和表征。

• 批准号: 10312413
• 负责人: MICHELLE E EHRLICH
• 金额: $ 16.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312413
• 关键词: ARNT gene; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid Fibrils; Amyloid beta-Protein; Biological; Biological Assay; Cerebrospinal Fluid; Characteristics; Data; Disease; Etiology; Exhibits; Foundations; Future; G-Protein-Coupled Receptors; Genes; Genomics; Human; Induced pluripotent stem cell derived neurons; Late Onset Alzheimer Disease; Ligands; Molecular; Molecular Profiling; Neurites; Neurofibrillary Tangles; Neuroglia; Neurons; Orphan; Parents; Peptide Receptor; Peptides; Physiological; Physiology; Play; Process; Research Personnel; Role; System; Therapeutic; disease heterogeneity; disorder subtype; extracellular; molecular subtypes; parent grant; receptor; small molecule

Project summary Alzheimer's disease (AD) pathology is characterized by the accumulation of neurofibrillary tangles, dystrophic neurites, and abundant extracellular fibrils of amyloid-β peptide. However, the etiology of typical late onset AD remains elusive. Over 20 genes have been associated with late onset AD, and this heterogeneity complicates the task of discovering disease modifying treatments. The parent application proposed to: (i) identify robust molecular subtypes of AD and their characteristic molecular signatures across different layers of Omics data; (ii) characterize molecular subtypes of AD by molecular signatures, multiscale regulatory networks and key drivers; (iii) evaluate genomic and functional impact of key drivers using human iPSC derived neurons and glia; and (iv) validate key drivers of molecular networks underlying AD subtypes. Recently, efforts by the investigators in the parent grant led to the identification of the VGF gene as a key driver of the network predicted to be altered in AD. However, the molecular mechanism by which VGF modulates the network altered in AD is not well understood. It is possible that receptor systems activated by peptides derived from VGF play a crucial role in this process. Support for this comes from our previous studies of another key driver, PREPL, where we found that decreases in PREPL expression leads to decreases in levels of secreted VGF- derived peptides. Also, several VGF-derived peptides have been detected in the cerebro-spinal fluid of AD subjects and many of these peptides exhibit distinct biological activities. This suggests the existence of receptors for the VGF-derived peptides and an important role for them in AD. To date receptors for the majority of these peptides have not been definitively identified. In this supplement we propose to carry out studies to identify neuronal receptors to 18 VGF-derived peptides using the PRESTO-TANGO® assay system that contains 302 G protein-coupled receptors including 135 listed as “orphan” receptors. Identification of these receptors is a prerequisite to studies investigating the physiological significance of VGF-derived peptides to AD as well as to identifying small molecules targeting these receptors, which could become potential therapeutics for the treatment of AD.

项目摘要 阿尔茨海默病（AD）病理学的特征在于神经元缠结的积累、营养不良性神经元损伤和神经元损伤。 神经突和丰富的淀粉样β肽胞外纤维。然而，典型的晚发性AD的病因 仍然难以捉摸超过20个基因与晚发性AD相关，这种异质性使AD的发病率增加。 发现疾病改善疗法的任务。该母申请建议：（一）确定稳健的 AD的分子亚型及其跨组学数据不同层的特征性分子签名; (ii)通过分子特征、多尺度调控网络和关键酶来表征AD的分子亚型 （iii）使用人iPSC衍生的神经元和神经胶质评估关键驱动因子的基因组和功能影响; 以及（iv）验证AD亚型的分子网络的关键驱动因素。最近， 研究人员在父母补助金导致VGF基因作为网络的关键驱动程序的鉴定 预测在AD中发生改变。然而，VGF调节网络的分子机制 在AD中改变并不容易理解。有可能受体系统激活的肽来源于 VGF在这一过程中发挥了关键作用。支持这一点的是我们之前对另一个关键驱动因素的研究， PREPL，我们发现PREPL表达的降低导致分泌的VGF水平的降低。 衍生肽。此外，在AD的脑脊液中检测到几种VEGF衍生的肽 受试者和许多这些肽显示出不同的生物活性。这表明， VEGF衍生肽的受体及其在AD中的重要作用。到目前为止，大多数人的受体 这些肽还没有被明确鉴定。在本补编中，我们建议进行研究， 使用PRESTO-TANGO®测定系统鉴定18种VEGF衍生肽的神经元受体， 含有302个G蛋白偶联受体，包括135个被列为“孤儿”受体。识别这些 受体是研究VEGF衍生肽对AD的生理意义的先决条件 以及识别靶向这些受体的小分子，这可能成为潜在的治疗方法。 用于治疗AD。