Molecular Assessment of Cause and Consequence of Cellular Senescence in Diverse Midbrain Cell Types in Parkinson's Disease

帕金森病多种中脑细胞类型细胞衰老原因和后果的分子评估

• 批准号: 10662519
• 负责人: Markus Riessland
• 金额: $ 39.35万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662519
• 关键词: AT Rich Sequence; Ablation; Adaptive Immune System; Address; Age Years; Binding Proteins; Brain; Cell Aging; Cell Nucleus; Cell model; Cells; Cellular Stress; Clinical; Coculture Techniques; Creativeness; Cues; DNA Damage; Development; Eating; Encephalitis; Endothelial Cells; Fostering; Functional disorder; Genetic; Goals; Health protection; Human; Immune; Immune response; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Innate Immune System; Lead; Mediating; Methods; Microglia; Midbrain structure; Mission; Mitochondria; Mitotic; Molecular; Monitor; Mus; Mutation; Nerve Degeneration; Neuroglia; Neurons; Outcome; Outcome Study; Paraquat; Parkinson Disease; Parkinson' s Disease Pathway; Parkinsonian Disorders; Pathology; Pathway interactions; Patients; Phenotype; Play; Prevalence; Prevention; Proliferating; Public Health; Research; Risk Factors; Role; Route; Signal Transduction; Sorting; Stress; Substantia nigra structure; Symptoms; TP53 gene; Time; Toxin; Tremor; United States National Institutes of Health; age related neurodegeneration; alpha synuclein; cell type; disease phenotype; dopaminergic neuron; experimental study; immune activation; in vivo; innovation; motor symptom; mutant; neuron loss; neuroprotection; novel; pars compacta; postmitotic; posture instability; prevent; programs; recruit; release factor; response; senescence; single nucleus RNA-sequencing; sporadic Parkinson' s Disease; stem cells; tool

PROJECT SUMMARY/ABSTRACT Parkinson's disease is the second most common age-related neurodegenerative disorder. The underlying cause of idiopathic Parkinson's is unknown. Importantly, prodromal inflammation of the midbrain has been found but remains unexplained. Recently, we have discovered that dopaminergic neurons can enter a state of cellular senescence and found significantly elevated numbers of senescent cells in the midbrain of human Parkinson's disease patients. Cellular senescence is a program that gets activated upon DNA damage signaling and prevents mitotic cells from uncontrolled proliferation. Most senescent cells express the so-called senescence associated secretory phenotype. This phenotype is characterized by the secretion of proinflammatory factors that recruit immune cells and signal “come here and eat me!”. We have also found that senescent human and mouse dopaminergic neurons secrete pro-inflammatory factors and get removed by activated glial cells. The rationale underlying this proposal is that cellular senescence is a generic mechanism in the midbrain leading to dopamine neuron loss which results in Parkinson's disease. The three aims of the proposal focus on 1) unravelling the parkinsonism-related in vitro triggers of cellular senescence in dopaminergic neurons; 2) the characterization of senescence-mediated activation of immune responses and the in vitro spreading of senescence between cell types of the midbrain; and 3) the in vivo induction and spreading of senescence between diverse cell types in the midbrain. In the proposed study, we will identify pathways that induce cellular senescence in dopaminergic neurons and identify factors which are crucial for the spreading of senescence and the activation of an immune response. Finally, we will assess whether ablation of senescent cells in the midbrain at the right time point will interfere with the spreading and can thereby ameliorate the loss of dopaminergic neurons of the midbrain. The molecular understanding of the induction of senescence as well as the identification of released factors that are important to trigger brain inflammation will shed light on the general pathomechanism of Parkinson’s disease and other age-related neurodegenerative disorders. Moreover, our findings will have direct clinical implications to eventually develop methods to interfere with midbrain senescence to ameliorate the progression of Parkinson’s disease.

项目概要/摘要 帕金森病是第二常见的与年龄相关的神经退行性疾病。 重要的是，特发性帕金森病的前驱炎症已被发现，但仍然存在。 最近，我们发现多巴胺能神经元可以进入细胞衰老状态。 发现人类帕金森病患者中脑中的衰老细胞数量显着增加。 细胞衰老是一个在 DNA 损伤信号传导后被激活并阻止有丝分裂细胞的程序。 大多数衰老细胞表现出所谓的衰老相关的分泌表型。 这种表型的特点是分泌促炎因子，招募免疫细胞并发出信号 “过来吃我！”我们还发现衰老的人类和小鼠多巴胺能神经元会分泌多巴胺能神经元。 促炎因子并被激活的神经胶质细胞清除，这一提议的基本原理是： 细胞衰老是中脑中导致多巴胺神经元损失的通用机制，从而导致 该提案的三个目标集中于 1) 阐明与帕金森病相关的体外触发因素。 多巴胺能神经元的细胞衰老；2) 衰老介导的激活的表征； 免疫反应和中脑细胞类型之间衰老的体外扩散；3) 体内； 在拟议的研究中，我们将研究中脑不同细胞类型之间衰老的诱导和扩散。 确定诱导多巴胺能神经元细胞衰老的途径，并确定对多巴胺能神经元细胞衰老至关重要的因素 最后，我们将评估衰老的扩散和免疫反应的激活是否会消失。 中脑中的衰老细胞在正确的时间点会干扰传播，从而改善 中脑多巴胺能神经元的丧失以及衰老诱导的分子理解。 因为识别出对引发脑部炎症很重要的释放因子将有助于揭示一般情况 此外，我们的发现还包括帕金森病和其他与年龄相关的神经退行性疾病的病理机制。 将具有直接的临床意义，最终开发出干扰中脑衰老的方法 改善帕金森病的进展。