Roles for astrocytic RIPK3 signaling in Parkinson's disease pathogenesis

星形细胞 RIPK3 信号在帕金森病发病机制中的作用

基本信息

批准号：
10536778
负责人：
Nydia Poshain Chang
金额：
$ 3.67万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
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：
https://reporter.nih.gov/project-details/10536778
关键词：
Ablation Alzheimer&apos s Disease Animal Model Astrocytes Behavior assessment Biology Cell Death Clinical Complex Corpus striatum structure Cues Disease Dopamine Dopaminergic Cell Functional disorder Gene Expression Genetic Genetic Transcription Health Image Impaired cognition Inflammatory Intervention Investigation Laboratories MPTP model Mediator of activation protein Midbrain structure Molecular Molecular Biology Molecular Target Motor Necrosis Nerve Degeneration Neuraxis Neurites Neurodegenerative Disorders Neuroglia Neurons Neuropathogenesis Parkinson Disease Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Pharmacogenetics Pharmacology Play Pre-Clinical Model Process Protein Kinase Proteomics RIPK1 gene Role Shapes Signal Transduction Substantia nigra structure Synapses System Testing Therapeutic Toxin United States Work axonal degeneration cell type cost estimate design dopaminergic neuron experimental study in vivo innovation motor behavior motor deficit mouse genetics mouse model neuroinflammation neuron loss neurotoxic nigrostriatal pathway novel overexpression pars compacta preservation response targeted treatment therapeutic development therapeutic target tool transcriptomics

项目摘要

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder of global concern, imposing an estimated cost of $52 billion per year in the United States, alone. The pathological hallmarks of PD include debilitating motor deficits, driven by progressive degeneration of dopaminergic neurons in the nigrostriatal pathway, an essential circuit for motor function. Emerging evidence suggests that neuroinflammation is a key player in the pathophysiology of this degenerative process. Astrocytes are the most abundant glial cells in the central nervous system (CNS), where they serve diverse homeostatic functions. However, following inflammatory stimulation, astrocytes enter a reactive state that can be neurotoxic, resulting in neuronal cell death. Numerous studies have now revealed that reactive astrocytes can contribute to clinical neurodegenerative diseases. However, the mechanism through which homeostatic astrocytes become reactive require further investigation. The central purpose of this proposal is to identify cellular and molecular mechanisms that promote astrocyte activation in the context of neurodegeneration. Recent work from our laboratory and others has identified receptor-interacting protein kinase-3 (RIPK3) as a central mediator of neuroinflammation. Here, we hypothesize that inflammatory RIPK3 signaling can induce astrocyte activation, leading to downstream neurotoxic effects and neuron loss in the midbrain. To test this hypothesis, I will utilize novel mouse genetic systems in which RIPK3 can be specifically deleted, overexpressed, or selectively activated in astrocytes. Studies in Aim 1 will examine how RIPK3 activity in astrocytes shapes transcriptional and functional responses associated with neurotoxic astrocyte activation. Aim 2 will examine whether astrocytic RIPK3 signaling can drive key molecular features of PD pathogenesis, including dopaminergic axon degeneration and reduction of dopamine release in the striatum. Together, these experiments aim to identify RIPK3 signaling as a vital mechanism of neurotoxic astrocyte activation and establish roles for this pathway in the pathophysiology of PD. Identifying these cell type-specific molecular mechanisms of Parkinsonian neurodegeneration are of vital importance for developing targeted PD therapeutics.

抽象的帕金森病 (PD) 是一种全球关注的神经退行性疾病，预计花费 52 美元仅在美国每年就有 10 亿人患有帕金森病，其病理特征包括运动功能障碍、由黑质纹状体通路中多巴胺能神经元的进行性退化驱动，黑质纹状体通路是新的证据表明神经炎症是病理生理学的关键因素。这种退化过程。星形胶质细胞是中枢神经系统（CNS）中最丰富的神经胶质细胞，然而，在炎症刺激后，星形胶质细胞进入。大量研究表明，这种反应状态可能具有神经毒性，导致神经细胞死亡。反应性星形胶质细胞可能导致临床神经退行性疾病，但其机制是通过的。哪些稳态星形胶质细胞变得活跃需要进一步研究该提案的中心目的。是确定在以下情况下促进星形胶质细胞激活的细胞和分子机制我们实验室和其他人最近的工作已经确定了受体相互作用蛋白。激酶 3 (RIPK3) 作为神经炎症的中心介质，在这里，我们将炎症 RIPK3 称为“炎症”。信号传导可以诱导星形胶质细胞激活，导致下游神经毒性作用和神经元损失为了验证这一假设，我将利用新的小鼠遗传系统，其中 RIPK3 可以被特异性地作用于中脑。目标 1 中的研究将检查 RIPK3 的活性如何。星形胶质细胞形成与神经毒性星形胶质细胞激活相关的转录和功能反应。目标 2 将检查星形细胞 RIPK3 信号传导是否可以驱动 PD 发病机制的关键分子特征，包括多巴胺能轴突变性和纹状体中多巴胺释放的减少。实验旨在确定 RIPK3 信号传导是神经毒性星形胶质细胞激活的重要机制，并建立确定该通路在 PD 病理生理学中的作用。帕金森神经变性的研究对于开发靶向帕金森病疗法至关重要。