The contribution of p16-expressing cells to tauopathy

p16 表达细胞对 tau 蛋白病的贡献

基本信息

批准号：
9904307
负责人：
Darren Baker
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904307
关键词：
AP20187 Address Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Animals Architecture Attenuated Behavioral Biological Markers Brain Brain region CDKN2A gene Cell Aging Cell Cycle Arrest Cells Cellular biology Chronic Clinical Complex Data Deposition Deterioration Disease Disease Progression Drug usage Elderly Elements Excision Exhibits Functional disorder Ganciclovir Genetic Models Goals Growth Factor Hippocampus (Brain)Human Inflammatory Intervention Kinetics Knowledge Life Longevity Matrix Metalloproteinases Mediating Memory Loss Mind Modeling Molecular Mus Mutant Strains Mice Mutate Names Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Onset of illness Organ Outcome Pathogenesis Pathologic Pathology Peptide Hydrolases Peptides Pharmaceutical Preparations Phenotype Preventive Intervention Process Production Public Health Reporter Research Risk Factors Sampling Senile Plaques Severity of illness Short-Term Memory Site Tauopathies Testing Therapeutic Therapeutic Intervention Tissues Transcription Alteration Transgenes Transgenic Mice Weaning Work abeta accumulation age related aged associated symptom base cell type chemokine cytokine design effective therapy entorhinal cortex healthspan human disease hyperphosphorylated tau in vivo mouse model novel premature prevent senescence synthetic drug tau Proteins tau aggregation tau mutation theories therapy development

项目摘要

Project Summary Advanced age is the main risk factor for most chronic human diseases, including tauopathies and Alz- heimer's disease (AD). However the molecular mechanisms underlying the exponential increases later in life remain largely unknown, impeding the development of interventions that prevent or attenuate disease. It has been proposed that senescent cells, which accumulate with aging in many tissues and organs and at sites of age-related pathologies, promote tissue dysfunction. AD is characterized by the accumulation of Aβ peptide- containing plaques and aggregates of hyper-phosphorylated or misfolded tau. Cells with features reminiscent of senescence have been observed in post mortem AD patient samples, however when these cells were ac- quired in the disease process and their contribution to pathology is unknown. Senescent cells are not merely residents of aged tissues, they develop a complex phenotype, termed the senescence-associated secretory phenotype (SASP), in which they secrete numerous growth factors, cytokines, and proteases that disrupt the architecture and functionality of neighboring cells in the tissue. The critical barrier to testing the idea that se- nescence is implicated in AD in vivo has been the lack of a mouse model that allows for selective elimination of senescent cells. We made use of a biomarker for senescence, p16Ink4a, to generate a novel transgene, INK- ATTAC, which removes p16Ink4a-positive senescent cells upon administration of a synthetic drug. We have fo- cused our studies firstly on understanding whether pathologic tau accumulation drives senescence in a tauopa- thy mouse model. In preliminary studies using a mouse model expressing a mutated form of human tau, we find that elimination of senescent cells prior to disease onset reduces neurofibrillary tangle deposition, neuro- degeneration and memory loss. With these results in mind, we will test our central hypothesis that senescent cells are causally implicated in tau pathology and that removal of senescent cells will have a profound disease- attenuating impact. We propose three specific aims. In the first aim we will determine the identity of the cells that senesce in this model as well as the kinetics of senescent cell accumulation. In the second aim, we will determine the nature and consequences of the secretory phenotype of senescent cells in the brain of our tau mutant model. In the third aim we will establish the therapeutic potential of senescent cell removal in tauopa- thy, where treatment to remove senescent cells is started after disease is established. The overall impact of this project is that it will critically test the untested hypothesis that senescent cells promote neurodegeneration, address key fundamental questions about disease-related senescent cells, identify key components of the SASP that promote tauopathy, and test the entirely novel concept of targeting senescent cells or key elements of the SASP as a therapeutic strategy for tau-mediated disease. This knowledge will pave the way towards transformative clinical interventions for treating or preventing not only tau-dependent disease, but also a broad spectrum of human age-related diseases that limit healthspan, in addition to conceptually advancing the fields of senescent cell biology.

项目摘要高年龄是大多数慢性人类疾病的主要危险因素，包括tauopathies和alz-- 海默氏病（AD）。然而，指数级增长的分子机制在以后的生活中增加在很大程度上未知，阻碍了预防或减轻疾病的干预措施的发展。它有我们被提出，在许多组织和器官中以及在与年龄相关的病理，促进组织功能障碍。 AD的特征是Aβ肽的积累含有磷酸化或错误折叠的tau的斑块和聚集体。具有特征的细胞提醒在验尸后的患者样品中已经观察到了感应的，但是当这些细胞被添加时疾病过程中所必需的及其对病理的贡献尚不清楚。衰老细胞不仅是老年组织的居民，他们发展出复杂的表型，称为衰老相关分泌表型（SASP），它们在其中秘密众多生长因子，细胞因子和蛋白酶破坏了组织中相邻细胞的结构和功能。测试这一想法的关键障碍在体内AD中暗示的是缺乏小鼠模型，该模型允许选择性消除感觉细胞。我们利用生物标志物来感应p16ink4a，生成一种新颖的变换，墨水 - ATTAC，它在施用合成药物后去除P16INK4A阳性的感觉细胞。我们有fo- 首先了解了我们的研究，了解病理tau的积累是否会驱动陶波中的衰老你的鼠标模型。在使用表达突变形式的人tau的小鼠模型的初步研究中，我们发现在疾病发作之前消除感觉细胞会减少神经纤维缠结的沉积，神经 - 退化和记忆丧失。考虑到这些结果，我们将测试我们的中心假设有时在tau病理学中隐含细胞，去除感觉细胞将具有深刻的疾病 - 减弱影响。我们提出了三个具体目标。在第一个目标中，我们将确定单元的身份该模型中的传感器以及感觉细胞积累的动力学。在第二个目标中，我们将确定tau大脑中感觉细胞的秘书表型的性质和后果突变模型。在第三个目标中，我们将确定在陶氏tauopa-中去除感觉细胞的治疗潜力您，在建立疾病后开始处理以去除感觉细胞的处理。的总体影响该项目是，它将批判性地检验未经测试的假设，即感觉细胞促进神经退行性，即解决有关疾病相关的感觉细胞的关键基本问题，确定关键组成部分促进tauopathy的SASP，并测试靶向感觉细胞或关键元素的完全新颖的概念 SASP作为TAU介导的疾病的治疗策略。这些知识将为通往用于治疗或预防tau依赖性疾病的变革性临床干预措施，而且还广泛除概念上推进领域外，还限制了与健康相关的人类相关疾病感觉细胞生物学。