Identification of protein targets of Smo signaling in cholinergic neurons that degenerate in Alzheimer’s Disease.

鉴定阿尔茨海默病中退化的胆碱能神经元中 Smo 信号传导的蛋白质靶标。

• 批准号: 10288823
• 负责人: Andreas H Kottmann
• 金额: $ 13.36万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288823
• 关键词: Ablation; Administrative Supplement; Adult; Affinity Chromatography; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amino Acids; Animals; Area; Atrophic; Award; Basal Ganglia; Basal Nucleus of Meynert; Brain; Brain-Derived Neurotrophic Factor; Cancer Etiology; Cell Nucleus; Cessation of life; Clinic; Cognitive deficits; Core Facility; Corpus striatum structure; Data; Denervation; Dose; Drug usage; Exhibits; Exposure to; Functional disorder; Funding; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Grant; Growth Factor; Harvest; Human Resources; Image; Impaired cognition; In Vitro; Interneurons; Label; Lead; Life; Maintenance; Mass Spectrum Analysis; Metabolic; Methionine-tRNA Ligase; Midbrain structure; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Oncogenic; Parkinson Disease; Pathologic; Pathology; Persons; Pharmaceutical Preparations; Pharmacology; Physiological; Post-Translational Protein Processing; Prosencephalon; Proteins; Proteome; Proteomics; Reagent; Research; Role; SHH gene; Sampling; Senile Plaques; Signal Transduction; Source; Synaptosomes; System; Technology; Tissues; Triad Acrylic Resin; Work; basal forebrain; basal forebrain cholinergic neurons; cholinergic; cholinergic neuron; cost; cyclopamine; dopaminergic neuron; drug development; in vivo; mouse model; neurochemistry; novel; pre-clinical; preoptic nucleus; side effect; smoothened signaling pathway; sonic hedgehog receptor; stem; tumor

This application seeks administrative supplement support for recently funded R21 AG065682-01 (award date 09/10/2020). The additional funding will allow the examination of Alzheimer’s Disease (AD) relevant brain nuclei in our otherwise Parkinson’s Disease (PD) focused analysis without expanding the scope, approach, or technology of the funded grant. Our funded research focuses on the role of Sonic Hedgehog (Shh), a cholinergic neuron trophic factor, in the cellular and neurochemical maintenance of the basal ganglia and its pathology in PD. We previously found that dopamine neurons of the mesencephalon (DAN) release Shh, which they use to communicate with cholinergic (CN) neurons in the striatum. Consistent with new imaging and preclinical findings that CN neurons degenerate in addition to DAN in PD, we found that the conditional ablation of Shh from DAN (ShhDAN-/-) results in adult onset neurodegeneration of CN. Our results suggests that boosting Shh effector activity in CN could promote CN survival and function in PD. The funded grant seeks to identify protein targets of ShhDAN signaling in CN of the striatum for the development of drugs that could protect CN from degeneration in PD. This work is enabled in our lab through in vivo metabolic labeling of mouse CN proteomes and the identification of ShhDAN dependent post-translational modifications via mass spectrometry. Our findings and approaches are also relevant to AD for three main reasons: (1) DAN also project outside of the basal ganglia to cholinergic neurons of the basal forebrain which degenerate in AD. (2) Recent imaging evidence reveals a significant loss of DANs in AD patients. Reduced levels of ShhDAN might therefore contribute to AD related CN degeneration. (3) Concordant, we found in preliminary results that ShhDAN-/- mice show a significant loss of CN in the basal forebrain. Together these findings suggest that effectors of ShhDAN signaling in CN of the basal forebrain could promote their survival. Here we seek funds that would allow us to include AD relevant tissues from the basal forebrain in our CN- specific proteomic analysis. The additional AD focused analysis would potentially identify targets of ShhDAN signaling unique to CN of the basal forebrain as well as targets relevant CN of both the striatum and basal forebrain. Thus, supplemental support would both deepen the interpretation of results obtained from the funded grant and in addition, potentially identify novel targets promoting CN survival in AD relevant brain nuclei.

本申请寻求对最近资助的R21 AG 065682 -01（授予日期）的行政补充支持 09/10/2020）。额外的资金将用于检查阿尔茨海默病（AD）相关的大脑 核在我们的其他帕金森病（PD）集中分析，而不扩大范围，方法， 资助的技术。 我们资助的研究重点是Sonic Hedgehog（Shh），一种胆碱能神经元营养因子，在 PD中基底神经节的细胞和神经化学维持及其病理学。我们之前发现， 中脑（DAN）的多巴胺神经元释放Shh，它们用来与胆碱能神经元进行交流。 (CN)纹状体的神经元与CN神经元退化的新成像和临床前发现一致 除了PD中的DAN之外，我们发现从DAN（ShhDAN-/-）条件性消融Shh导致成人PD中的DAN， CN的神经变性发作。我们的研究结果表明，提高CN中Shh效应子的活性可以促进 PD中CN的存活和功能。资助的赠款旨在确定CN中ShhDAN信号传导的蛋白质靶点， 纹状体的药物开发，可以保护CN从PD的退化。这项工作是启用 在我们实验室通过小鼠CN蛋白质组的体内代谢标记和ShhDAN的鉴定， 依赖性翻译后修饰。 我们的研究结果和方法也与AD相关，主要有三个原因：（1）DAN也投射在 基底神经节到基底前脑的胆碱能神经元，其在AD中退化。(2)近期成像 有证据显示AD患者的DAN显著丢失。因此，ShhDAN水平的降低可能 导致AD相关CN变性。(3)一致的是，我们在初步结果中发现，ShhDAN-/- 小鼠在基底前脑中显示出CN的显著损失。这些发现表明， 基底前脑CN区的ShhDAN信号能促进其存活。 在这里，我们寻求资金，使我们能够包括AD相关组织从基底前脑在我们的CN- 特异性蛋白质组学分析。额外的AD重点分析可能会识别ShhDAN的目标 基底前脑的CN特有的信号传导以及靶向纹状体和基底前脑的相关CN 前脑因此，补充支助既可以加深对受资助项目成果的解释， 此外，还可能发现促进AD相关脑核中CN存活的新靶点。