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。

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

该申请为最近资助的R21 AG065682-01寻求行政补充支持（奖励日期 09/10/2020）。额外的资金将允许检查阿尔茨海默氏病（AD）相关的大脑我们原本帕金森氏病（PD）的核心核心分析，而没有扩大范围，方法或资助赠款的技术。我们资助的研究侧重于胆碱能神经营养因子Sonic刺猬（SHH）的作用 Bassal神经节的细胞和神经化学维持及其在PD中的病理。我们以前发现 Messencephalon（DAN）发行的多巴胺神经元SHH与胆碱能进行交流（CN）纹状体中的神经元。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外，我们还发现Dan（Shhdan - / - ）的SHH有条件消融会导致成人 CN的发作神经变性。我们的结果表明，CN中提高SHH效应子活性可以促进 CN生存和功能在PD中。资助的赠款旨在确定CN中Shhdan信号传导的蛋白质靶标可以保护CN免受PD变性的药物开发的纹状体。这项工作已启用通过小鼠CN蛋白质组的体内代谢标记和Shhdan的鉴定，在我们的实验室中通过质谱法进行了依赖的翻译后修饰。我们的发现和方法也与广告有关，原因有三个主要原因：（1）DAN在基底神经元的基底神经神经元，该神经元在AD中退化。（2）最近的成像证据表明，AD患者的DAN大幅损失。因此，Shhdan的水平降低了有助于与AD相关的CN变性。（3）一致的，我们在初步结果中发现了shhdan - / - 小鼠在基本前脑中表现出明显的CN损失。这些发现一起表明基本前脑CN中的Shhdan信号传导可以促进其生存。在这里，我们寻求资金，使我们能够在我们的CN-中包括基本前脑的广告相关时间特定的蛋白质组学分析。额外的集中分析将有可能识别Shhdan的目标基本前脑CN的信号传导以及纹状体和碱性的相关CN的靶标前脑。这是补充支持都可以加深对资助的结果的解释授予并另外，有可能识别促进AD相关脑核中CN存活的新型靶标。