Harnessing Molecular Networks of Resilience for Therapeutic Discoveries in AD

利用弹性分子网络进行 AD 治疗发现

• 批准号: 10404635
• 负责人: NILUFER ERTEKIN-TANER
• 金额: $ 113.04万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404635
• 关键词: Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Area; Astrocytes; Autopsy; Biological; Biological Markers; Biological Models; Biological Process; Biology; Blood Vessels; Brain; Cell Nucleus; Cells; Clinic; Clinical; Cognitive; Cohort Studies; Coin; Complex; Crystallization; DNA; Data; Databases; Development; Disease; Drug Targeting; Elderly; Ensure; Environmental Risk Factor; Etiology; Experimental Models; Functional disorder; Gene Proteins; Genetic; Genetic Transcription; Genotype; Human; Impaired cognition; Individual; Knowledge; Lead; Longitudinal Studies; Medicine; Microglia; Modeling; Molecular; Molecular Target; Multiomic Data; Natural Immunity; Nerve Degeneration; Neurons; Oligodendroglia; Organoids; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Peripheral; Persons; Pharmacogenomics; Positron-Emission Tomography; Predisposition; Proteins; Proteome; RNA; RNA Sequences; Sampling; Side; Specificity; Structure; System; Systems Biology; Temporal Lobe; Testing; Therapeutic; Time; Translating; Translations; United States National Institutes of Health; Validation; apolipoprotein E-4; base; brain cell; brain tissue; cell type; cohort; comorbidity; data tools; drug candidate; druggable target; genetic risk factor; human data; human old age (65+); induced pluripotent stem cell; mild cognitive impairment; myelination; neuropathology; novel; novel therapeutics; pathological aging; prophylactic; resilience; screening; therapeutic target; tool; transcriptome; transcriptome sequencing; whole genome

Although protection from and resilience to Alzheimer's disease (AD) constitute a fundamental aspect to understanding AD pathophysiology, this is a relatively understudied area and the molecular basis of resilience to AD is largely unknown. This is a critical knowledge gap, as uncovering biological pathways of resilience could lead to the discovery of novel therapeutic or prophylactic drug targets in AD. It is clear that there are individuals who may be protected from developing AD pathology, despite advanced age and having highly penetrant genetic risk factors for AD, such as APOE ε4 allele. Additionally, there are people with cognitive resilience who remain free of cognitive decline despite having pathologic or biomarker changes of AD. Current therapeutic discovery efforts in AD are largely focused on uncovering the biological pathways that are perturbed in this condition, the key molecules in these pathways, and identification of therapeutic compounds to stop and/or reverse these perturbations. These efforts are based on the hypothesis that concerted perturbations of molecular networks that serve key biological functions underlie the pathophysiology of many common, complex diseases including AD. While it is critically important to discover perturbed molecular networks in AD, this is only one side of the coin. We postulate that application of network biology approaches to investigate individuals who are protected from and resilient to AD can uncover novel biological pathways that underlie resilience to AD. In addition to revealing novel resilience pathways, study of resilient individuals is also critical for the validation of perturbed disease networks, as we expect some of the susceptibility and resilience networks to overlap but have opposite direction of effect. Such validation efforts are essential for the translation of these discoveries to viable drug targets. In this proposal, we plan to study individuals who are protected from and resilient to AD by leveraging samples from autopsied and living human cohorts, to utilize existing and generate new molecular data, including RNA sequence (RNAseq) and whole genome sequence (WGS), and to apply analytic approaches to identify resilience networks. We will utilize single-nucleus RNAseq (snRNAseq) to identify cell-specific molecular changes of resilience in brain and validate these using iPSC- based models. To translate this knowledge to therapeutic targets, we will apply novel pharmacogenomics tools. Our proposal is responsive to the RFA-AG-18-029 and aims to: 1) Identify molecular targets of resilience to development and propagation of AD pathology in an autopsy cohort enriched for older controls; 2) Identify molecular targets of cognitive resilience in the presence of AD biomarkers in a longitudinally assessed older cohort enriched for clinically normal individuals with positive amyloid PET and APOE ε34 or ε44 genotypes; 3) Validate cell-specific molecular changes in iPSC-based models; 4) Decipher druggable targets of AD resilience and potential therapeutic compounds using systems-based pharmacogenomics tools. We will integrate our findings with those from AMP-AD, M2OVE-AD, ADNI and ADSP and share all generated data and tools.

尽管对阿尔茨海默氏病（AD）的保护和韧性（AD）构成了一个基本方面 了解AD病理生理学，这是一个相对了解的领域，也是弹性的分子基础 广告基本上是未知的。这是一个关键的知识差距，因为发现了弹性的生物学途径 可能导致在AD中发现新型治疗或预防性药物靶标。显然有 可能受到保护免受AD病理学的保护，高龄和高度的个人 AD的渗透遗传危险因素，例如APOEε4等位基因。此外，还有认知的人 尽管有病理学或生物标志物的AD变化，但仍然没有认知能力下降的韧性。当前的 AD的治疗发现工作主要集中在发现生物学途径上 在这种情况下扰动，这些途径中的关键分子和治疗化合物的鉴定 停止和/或逆转这些扰动。这些努力是基于一致的假设 发挥关键生物学功能的分子网络的扰动是许多人的病理生理学的基础 常见的复杂疾病，包括AD。虽然发现扰动的分子非常重要 AD中的网络，这只是硬币的一侧。我们假设网络生物学方法的应用 调查受到保护的人，并弹性到AD可以发现新的生物学途径 这是对广告的韧性。除了揭示新颖的弹性途径外，对弹性人的研究是 我们期望的某些易感性和 弹性网络重叠，但效果方向相反。这种验证工作对于 这些发现转换为可行的药物靶标。在此提案中，我们计划研究 通过利用尸体尸体和生命人群的样本来保护和弹性到广告，以利用 现有并生成新的分子数据，包括RNA序列（RNASEQ）和整个基因组序列 （WGS），并采用分析方法来识别弹性网络。我们将利用单核RNASEQ （SNRNASEQ）确定脑中弹性的细胞特异性分子变化，并使用IPSC-验证它们 基于模型。为了将这些知识转化为治疗靶标，我们将应用新颖的药物基因组学 工具。我们的建议对RFA-AG-18-029的反应敏感，目的是：1）确定弹性的分子靶标 在尸检队列中发展和传播AD病理的发展和富含较旧对照的尸检； 2）识别 在纵向评估的AD生物标志物存在下，认知弹性的分子靶标 队列富含淀粉样蛋白阳性PET和APOEε34或ε44基因型的临床正常个体； 3） 在基于IPSC的模型中验证细胞特异性分子变化； 4）AD弹性的破译靶标 以及使用基于系统的药物基因组学工具的潜在治疗化合物。我们将整合我们的 来自AMP-AD，M2OVE-AD，ADNI和ADSP的发现，并共享所有生成的数据和工具。

项目成果

Effects of sex and APOE on Parkinson's Disease-related cognitive decline.

性别和 APOE 对帕金森病相关认知能力下降的影响。

• DOI: 10.5603/pjnns.a2021.0071
• 发表时间: 2021
• 期刊: Neurologia i neurochirurgia polska
• 影响因子: 2.9
• 作者: Tipton,PhilipW;Bülbül,Nazli;Crook,Julia;Quicksall,Zachary;Ross,OwenA;Uitti,RyanJ;Wszolek,ZbigniewK;Ertekin-Taner,Nilüfer
• 通讯作者: Ertekin-Taner,Nilüfer