Environmental exposure and astrocytic senescence: novel link to PD?

环境暴露和星形细胞衰老：与 PD 的新联系？

基本信息

批准号：
8758627
负责人：
Julie Kay Andersen
金额：
$ 29.1万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8758627
关键词：
Address Affect Aging Animal Model Astrocytes Attention Bioavailable Biological Biological Markers Cell Aging Cell Proliferation Cells Collaborations Coupled Data Development Disease Environmental Exposure Epidemiology Etiology Event Excision Exposure to Future Genetic Predisposition to Disease Growth Factor Human In Vitro Incidence Inflammatory Institutes Iron Laboratories Libraries Link Longevity Malignant - descriptor Malignant Neoplasms Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Measure Oxidative Stress Paraquat Parkinson Disease Pathology Pathway interactions Peptide Hydrolases Peripheral Phenotype Play Population Process Research Risk Risk Factors Role Screening Result Stress Structure System Testing Tissues Toxic Environmental Substances age related aging brain base brain cell cell type cytokine disorder risk dopaminergic neuron environmental agent in vivo man mouse model nerve stem cell nervous system disorder neuropathology novel prevent public health relevance response screening senescence small molecule small molecule libraries stressor success therapeutic target therapy development toxicant

项目摘要

DESCRIPTION (provided by applicant): Cellular senescence prevents the proliferation of mitotically-competent cells in the periphery in response to various stressors, including endogenous oxidative stress. Senescent cells express a 'senescence- associated secretory phenotype' or SASP, involving the secretion of pro-inflammatory factors that can cause degeneration of neighboring cells. While cell senescence in peripheral tissues has recently been shown to result in a number of age-related pathologies, whether it plays a causal role in brain aging and neurodegenerative disease is currently unknown. Preliminary data from our laboratory suggests that induction of astrocytic senescence may contributes significantly to neurodegeneration associated with Parkinson's disease (PD) and that this can be induced by candidate environmental toxicants previously linked to increased risk for PD. We propose to use two available environmental toxicant libraries to perform a small molecule screen in order to identify additional senescence-inducing agents, paying particular attention to bioavailable compounds previously associated with risk for PD. This will form the basis of future studies assessing the ability of environmental toxins identified in the screen to induce astrocytic senescence in vivo and its contribution to PD neuropathology. Based on this data, we plan to test the hypothesis that environmental agents may increase risk for PD in part via induction of astrocytic senescence that can in turn impact on PD-related neurodegeneration. If correct, our hypothesis has the potential to transform how we think about and treat PD and other related neurological disorders.

描述（由申请人提供）：细胞衰老阻止外周具有有丝分裂能力的细胞响应各种应激源（包括内源性氧化应激）而增殖。衰老细胞表达“衰老相关的分泌表型”或SASP，涉及可导致邻近细胞退化的促炎因子的分泌。虽然最近已证明外周组织中的细胞衰老会导致许多与年龄相关的病理，但目前尚不清楚它是否在大脑衰老和神经退行性疾病中发挥因果作用。我们实验室的初步数据表明，星形细胞衰老的诱导可能会显着导致与帕金森病 (PD) 相关的神经变性，并且这可能是由先前与帕金森病风险增加相关的候选环境毒物引起的。我们建议使用两个可用的环境毒物库进行小分子筛选，以识别其他衰老诱导剂，特别注意先前与帕金森病风险相关的生物可利用化合物。这将构成未来研究的基础，评估筛选中确定的环境毒素诱导体内星形胶质细胞衰老的能力及其对帕金森病神经病理学的贡献。基于这些数据，我们计划检验这样的假设：环境因素可能部分通过诱导星形胶质细胞衰老而增加帕金森病的风险，而星形细胞衰老反过来又会影响帕金森病相关的神经变性。如果正确，我们的假设有可能改变我们对帕金森病和其他相关神经系统疾病的看法和治疗方式。