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: 10521877
• 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/10521877
• 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; Cues; DNA Damage; Development; Eating; Encephalitis; Endothelial Cells; Fostering; Functional disorder; Genetic; Goals; Health; Human; Immune; Immune response; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Lead; Light; 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; Public Health; Research; Risk Factors; Role; Route; Signal Transduction; Sorting - Cell Movement; 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; innovation; motor symptom; mutant; neuron loss; novel; pars compacta; posture instability; prevent; programs; recruit; release factor; response; senescence; stem cells; tool; transcriptome sequencing; 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; Cues; DNA Damage; Development; Eating; Encephalitis; Endothelial Cells; Fostering; Functional disorder; Genetic; Goals; Health; Human; Immune; Immune response; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Lead; Light; 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; Public Health; Research; Risk Factors; Role; Route; Signal Transduction; Sorting - Cell Movement; 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; innovation; motor symptom; mutant; neuron loss; novel; pars compacta; posture instability; prevent; programs; recruit; release factor; response; senescence; stem cells; tool; transcriptome sequencing

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.

项目摘要/摘要 帕金森氏病是第二常见的与年龄有关的神经退行性疾病。的根本原因 特发性帕金森氏症是未知的。重要的是，已经发现了中脑的前驱炎症，但仍存在 无法解释。最近，我们发现多巴胺能神经元可以进入细胞感应状态，并且 发现在人类帕金森氏病患者中脑中，感觉细胞数量显着升高。 细胞感应是一种在DNA损伤信号传导下激活的程序，并防止有丝分裂细胞 不受控制的增殖。大多数感觉细胞表达了所谓的感应相关的秘密表型。 该表型的特征是促炎性因子的分泌，这些因素募集了免疫电池和信号 “来这里吃我！”。我们还发现感觉人和小鼠多巴胺能神经元秘密 促炎性因素，并通过活化的神经胶质细胞去除。该提议的基本原理是 细胞感应是中脑的一种通用机制，导致多巴胺神经元丧失，导致 帕金森氏病。该提案的三个目的重点是1）揭开与帕金森氏症有关的体外触发因素 多巴胺能神经元中的细胞感应； 2）感应介导的激活的表征 免疫反应和中脑细胞类型之间的感受的体外传播； 3）体内 中脑中潜水细胞类型之间的诱导和传播。在拟议的研究中，我们将 确定诱导多巴胺能神经元中细胞感应的途径，并确定对对的因素，这些因素对于 感应的传播和免疫反应的激活。最后，我们将评估是否消融 正确时间点中脑中的感觉细胞会干扰扩散，从而改善该扩散 中脑多巴胺能神经元的丧失。对诱导感应的分子理解 由于鉴定释放因素对触发脑感染很重要的因素将揭示一般 帕金森氏病和其他与年龄有关的神经退行性疾病的病理机制。而且，我们的发现 将具有直接的临床意义，最终开发出干扰中脑感应的方法 改善帕金森氏病的进展。