Mechanisms of age-related tauopathy

年龄相关 tau 蛋白病的机制

基本信息

批准号：
10586796
负责人：
John Fonda Crary
金额：
$ 248.16万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586796
关键词：
Adaptor Signaling Protein Aging Algorithms Alzheimer&apos s Disease Amyloid beta-Protein Amyloidosis Autopsy Axon Biochemical Biological Markers Candidate Disease Gene Categories Cell Death Cell model Cells Chromosome 4 Clinical Collection Data Data Set Diagnosis Enzyme-Linked Immunosorbent Assay Event Expression Profiling Genetic Genetic Risk Gliosis Goals Gold Grain Hippocampus (Brain)Histologic Human Immunofluorescence Immunologic Immunohistochemistry Individual Investigation Lead Lesion Literature Measures Medical Genetics Molecular Nerve Degeneration Neurofibrillary Tangles Neurons Pathogenesis Pathologic Pathology Patients Play Process Proteins Public Health Reproducibility Research Risk Role Scientist Series Staging Synapses Tauopathies Testing Therapeutic Tissue Banks Tissues Toxic effect Training Ubiquitin Vision Work abeta deposition age related aged base brain tissue burden of illness clinical biomarkers clinical predictors cohort convolutional neural network deep learning endophenotype functional disability functional genomics genetic association human tissue improved in vivo innovation insight neural network neuron loss neuropathology novel novel marker novel therapeutics protective allele risk variant symptomatology tau Proteins tau mutation trait transcriptomics whole slide imaging

项目摘要

ABSTRACT In 2014, we proposed criteria for a new category of Alzheimer disease (AD) neuropathological change describing subjects with AD-type neurofibrillary tangles without significant amyloid-beta (Aβ) deposition. This autopsy designation, termed primary age-related tauopathy (PART), is the subject of increasing investigation, with studies suggesting that PART diverges in important ways from AD. There is a critical need to better understand what differentiates PART from other tauopathies and AD, which it mimics clinically and neuropathologically. We are assembling a large collection of brain tissues from aged individuals to enable histopathological, genetic and mechanistic molecular studies. We found that PART diverges pathoanatomically from other tauopathies with an unexpected selective vulnerability of different hippocampal subfields. Our data indicates that PART has genetic risk that partially overlaps with AD, uncovering an association with a locus on chromosome 4 containing JADE1, a multifunctional adaptor protein that regulates cell death. Here, we will expand this work to derive novel histopathological traits from our large collection to identify and validate additional risk alleles for PART and uncover novel mechanisms. Our long-term goal is to elucidate the events that underlie tauopathy through characterization of neurofibrillary changes on the cellular level for correlative clinical, biomarker, genetic, and molecular studies. The objective here is to leverage our unique tissue collection to generate novel pathoanatomical endophenotypes for functional genomic studies. We will deploy both classical and computational histopathological approaches. Our preliminary data indicate that computationally derived features more strongly predict functional impairment compared to the gold standard. Our central hypothesis is that patients with PART have a distinct constellation of cellular and molecular drivers that converge with AD with respect to tauopathy but diverge with respect to Aβ pathology. Our rationale is that better defining the neuropathology of PART will enable clinical and genetic associations that reveal mechanistic insights into neurofibrillary degeneration. We will accomplish our objectives by pursuing the following aims: Aim 1. To identify neuropathological signatures of PART and lay the groundwork for genetic and mechanistic studies. Aim 2. To identify risk alleles for PART. Aim 3. To test the hypothesis that candidate genes associated with PART play a mechanistic role in neurofibrillary degeneration. This research is significant because better delineating the features of PART in human post-mortem tissues will provide valuable insights into the cellular events associated with tauopathies. This project is innovative because it will lead to improved approaches for diagnosis and staging PART that more closely align with clinical symptomatology. This research represents a shift in the way we conceptualize tauopathy in aging, allowing us to more fully define the neurofibrillary cascade, providing valuable insights into the pathogenesis of tauopathies and paving the way towards novel biomarkers and therapeutics.

抽象的在2014年，我们提出了针对阿尔茨海默氏病（AD）神经病理学变化描述的新类别的标准具有AD型神经原纤维缠结的受试者，没有明显的淀粉样β（Aβ）沉积。此尸检指定称为初级年龄相关的tauopathy（一部分），是研究的主题。表明该部分以重要的方式分歧。有迫切需要更好地了解什么将部分与其他tauopathies和AD区分开，并在临床和神经病理学上模仿它们。我们是组装大量的脑组织，从老年个体，使组织病理学，遗传和机械分子研究。我们发现，部分与其他tauopathies相差不同海马子场的意外选择性脆弱性。我们的数据表明部分具有遗传风险部分与AD重叠的风险，发现与包含JADE1的染色体上的一个基因座的关联，调节细胞死亡的多功能衔接蛋白。在这里，我们将扩大这项工作以推导小说我们大型收藏中的组织病理学特征，以识别和验证部分和发现新颖的机制。我们的长期目标是阐明通过tauopathy的事件相关临床，生物标志物，遗传学和分子研究。这里的目的是利用我们独特的组织收集来产生小说用于功能基因组研究的途径本质型。我们将部署古典和计算组织病理学方法。我们的初步数据表明计算得出的功能与黄金标准相比，更强烈预测功能障碍。我们的中心假设是具有部分部分的患者有一个明显的细胞和分子驱动因素，这些驱动因素与AD融合在一起尊重tauopathy，但相对于Aβ病理有所不同。我们的理由是更好地定义部分的神经病理学将使临床和遗传关联揭示机械洞察力神经原纤维变性。我们将通过追求以下目标来实现我们的目标：目标1。部分部分的神经病理学特征，为遗传和机理研究奠定了基础。目标2 确定部分的风险等位基因。目的3。检验以下假设：与一部分相关的候选基因发挥作用在神经纤维变性中的机械作用。这项研究很重要，因为更好地描述人类验尸组织中一部分的特征将为相关的细胞事件提供宝贵的见解带有tauopathies。该项目具有创新性，因为它将导致改进的诊断方法和分期的方法部分与临床症状学更加一致。这项研究代表了我们的方式转变在衰老中概念化tauopathy，使我们能够更全面地定义神经纤维级联洞悉陶氏病的发病机理，并为新颖的生物标志物和治疗铺平了道路。