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 2014 年，我们提出了新一类阿尔茨海默病 (AD) 神经病理变化的标准，描述了患有 AD 型神经原纤维缠结的受试者没有明显的淀粉样蛋白 - β (Aβ) 沉积。指定，称为原发性年龄相关 tau 病 (PART)，是越来越多研究的主题表明 PART 在重要方面与 AD 不同，迫切需要更好地理解什么。 PART 与其他 tau蛋白病和 AD 不同，它在临床和神经病理学上与我们相似。收集大量老年人的脑组织，以进行组织病理学、遗传和我们发现 PART 在病理解剖学上与其他 tau蛋白病不同。我们的数据表明 PART 具有遗传性。与 AD 部分重叠的风险，揭示了与包含 JADE1 的 4 号染色体上的基因座的关联，在这里，我们将扩展这项工作以衍生出新的调节细胞死亡的多功能接头蛋白。来自我们大量收集的组织病理学特征，用于识别和验证 PART 和我们的长期目标是通过揭示tau蛋白病背后的事件。神经原纤维在细胞水平上的变化特征，用于相关的临床、生物标志物、遗传和这里的目标是利用我们独特的组织收集来产生新的。我们将部署经典和功能基因组研究的病理解剖内表型。我们的初步数据表明计算得出的特征。与金标准相比，我们的中心假设是更强有力地预测功能障碍。 PART 患者具有一系列独特的细胞和分子驱动因素，这些驱动因素与 AD 一致与 tau 蛋白病相关，但与 Aβ 病理学不同，我们的理由是更好地定义 tau 蛋白病。 PART 的神经病理学将实现临床和遗传关联，揭示以下机制的见解我们将通过追求以下目标来实现我们的目标：目标 1. 确定 PART 的神经病理学特征并为遗传和机制研究奠定基础。目标 2。识别 PART 的风险等位基因目标 3. 检验与 PART 相关的候选基因发挥作用的假设。这项研究在神经原纤维变性中的机制作用具有重要意义，因为可以更好地描述神经原纤维变性。人类死后组织中 PART 的特征将为相关细胞事件提供有价值的见解该项目具有创新性，因为它将改进诊断和分期方法。与临床症状学更加一致的部分这项研究代表了我们方式的转变。将衰老过程中的 tau 蛋白病概念化，使我们能够更全面地定义神经原纤维级联，从而提供有价值的信息深入了解 tau蛋白病的发病机制，并为新型生物标志物和治疗方法铺平道路。