Novel pathogenetic mechanism for hippocampal sclerosis, a common Alzheimers mimic

海马硬化的新发病机制，一种常见的阿尔茨海默病模拟

• 批准号: 9402752
• 负责人: PETER T. NELSON
• 金额: $ 45.86万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 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/9402752
• 关键词: ABCC9 gene; Affect; Age; Aging; Agonist; Alzheimer' s Disease; American; Area; Astrocytes; Autopsy; Behavior; Biological Markers; Biometry; Blood specimen; Brain; Brain Diseases; Brain Pathology; Cell Culture Techniques; Cells; Clinical; Cognitive; DNA; Data; Databases; Dementia; Development; Diagnosis; Disease; Elderly; Exhibits; Functional disorder; Future; Gene Expression; Genes; Genetic; Genotype; Glimepiride; Goals; Hippocampus (Brain); Hormone Responsive; Human; Impaired cognition; Individual; Infarction; Interdisciplinary Study; Kentucky; Knockout Mice; Knowledge; Life; Link; Metformin; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Neurofibrillary Tangles; Oral; Pathogenesis; Pathologic; Pathology; Patient Self-Report; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Regulator Genes; Research; Research Personnel; Risk; Sampling; Severities; Spinal Puncture; Testing; Therapeutic; Thyroid Gland; Thyroid Hormones; Thyroxine; Transcript; Triiodothyronine; Universities; Widespread Disease; aged; base; biobank; cell transformation; clinical biomarkers; cohort; digital; experimental study; genetic variant; genomic biomarker; hippocampal sclerosis; human embryonic stem cell; human genomics; in vivo; neurobehavior; neuropathology; novel; novel marker; prevent; programs; protein TDP-43; risk variant; synucleinopathy; therapeutic target

Hippocampal sclerosis of aging (HS-Aging) is a major pathologic substrate of dementia but there currently are no validated strategies in the clinical setting to diagnose or treat the disease. HS-Aging affects ~15% of elderly persons and is associated with substantial cognitive impairment. Our group has studied this area extensively, leading to the following major hypothesis: thyroid hormone (TH) dysregulation contributes to HS-Aging pathogenesis. This novel pathogenetic mechanism may provide the basis to diagnose HS- Aging during life using CSF analyses, and to develop a therapeutic strategy. However, critical knowledge gaps remain in terms of characterizing the specific association between TH dysfunction and brain pathology, and the potential to target the mechanism for therapeutic purposes. We propose a research program to fill these knowledge gaps while testing key hypotheses via the following Specific Aims: Hypothesis 1: Clinical TH status is associated with presence and severity of HS-Aging pathology. Specific Aim 1: Test the hypothesis in a convenience sample (n=205, including cognitively intact and diverse non-HS-Aging dementia controls) from the University of Kentucky AD Center biobank. We will apply rigorous, quantitative digital pathologic methods to assess TDP-43 pathology, AD plaques/tangles, and α- synucleinopathy for correlation with clinical TH status: self-reported TH disease and TH medications are well- documented. As expected in aged persons, more than 25% of the subjects exhibited clinical TH dysfunction. Hypothesis 2: CSF TH levels are associated with HS-Aging pathology and may provide a novel biomarker. Specific Aim 2: Evaluate TH (triiodothyronine, or T3) in CSF as a clinical biomarker of HS-Aging. We will assess human CSF TH levels with direct correlation with various subtypes of pathology. We also will test TH in clinical CSF from lumbar punctures, correlated with established AD-related biomarkers (Aβ and tau) and HS-Aging SNPs, with the goal of developing a new method to diagnose HS-Aging in living persons. We have obtained CSF from autopsied individuals (n=104) and clinical CSF samples (n=195) to accomplish this Aim. Hypothesis 3: Specific HS-Aging risk-associated gene variants induce altered brain TH levels with extensive impact on brain gene expression, and orally available drugs can alter this pathogenetic mechanism. Specific Aim 3: Define gene expression changes relevant to TH and HS-Aging. We will analyze human genomics databases to define how gene changes linked to HS-Aging risk contribute to variability in ABCC9 and SLCO1C1 (a major brain TH transporter) expression. We will test human cells (cultured human hESC astrocytes and lymphoblastoid cells transformed with DNA from people with known genotypes and pathology) to determine the potential for manipulating the levels of ABCC9, of TH transporter SLCO1C1, and of other TH- regulated genes. Finally, in mice, we will test how TH-responsive gene expression, neuropathology, and neurobehavior are affected in vivo by treatment with TH and/or the ABCC9 agonist drug glimepiride.

老年性海马硬化(HS-Aging)是痴呆的主要病理基础，但目前有 在临床环境中没有有效的策略来诊断或治疗这种疾病。HS-老龄化影响约15% 而且与严重的认知障碍有关。我们小组对这一地区进行了研究 广泛地，导致以下主要假设：甲状腺激素(TH)失调 对HS-Aging发病机制的研究。这一新的致病机制可能为HS的诊断提供依据。 使用脑脊液分析来分析生命中的衰老，并开发治疗策略。然而，批判性知识 在表征TH功能障碍和大脑病理之间的具体联系方面仍然存在差距， 以及将该机制作为治疗目标的可能性。我们提出了一个研究计划来填补 这些知识差距通过以下具体目标检验关键假设： 假设1：临床TH状态与HS-Aging病理的存在和严重程度有关。 具体目标1：在方便的样本(n=205，包括认知完整和多样化的样本)中检验假设 非HS-老年性痴呆对照)，来自肯塔基大学AD中心生物库。我们将严格执行， 定量数字病理学方法评估Tdp-43病理、AD斑块/缠绕和α- 合并核病与临床TH状态的相关性：自我报告的TH病和TH药物治疗效果良好 有记录在案。在老年人中，如预期的那样，超过25%的受试者表现出临床TH功能障碍。 假设2：脑脊液TH水平与HS-Aging病理相关，并可能提供一种新的生物标志物。 具体目的2：评价脑脊液中TH(三碘甲腺原氨酸，或T3)作为HS-衰老的临床生物标志物。我们会 评估与不同病理亚型直接相关的人脑脊液TH水平。我们还将测试 在临床腰椎穿刺液中，与已建立的AD相关生物标志物(Aβ和Tau)和 HS-Aging SNPs，目的是开发一种诊断活体HS-Aging的新方法。我们有 为了实现这一目标，从尸检人员(n=104)和临床脑脊液标本(n=195)中获取脑脊液。 假设3：特定的HS-衰老风险相关基因变异导致广泛的脑组织TH水平改变 对大脑基因表达的影响，口服药物可以改变这种致病机制。 具体目标3：确定与TH和HS-衰老相关的基因表达变化。我们将分析人类 基因组学数据库，以确定与HS-衰老风险相关的基因变化如何影响ABCC9的可变性 和SLCO1C1(一个主要的脑TH转运体)的表达。我们将测试人类细胞(培养的人hESC 用已知基因型别和病理的人的DNA转化的星形胶质细胞和淋巴母细胞) 为了确定操纵ABCC9、转运蛋白SLCO1C1和其他转运蛋白水平的可能性- 受调控的基因。最后，在小鼠身上，我们将测试TH反应基因的表达、神经病理学和 在体内，TH和/或ABCC9激动剂药物格列美脲的治疗会影响神经行为。