Testing a therapeutic strategy for hippocampal sclerosis of aging, a key AD mimic

测试老年海马硬化的治疗策略，这是一种关键的 AD 模拟

• 批准号: 9055456
• 负责人: PETER T. NELSON
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055456
• 关键词: Address; Affect; Age; Aging; Agonist; Alzheimer' s Disease; Amygdaloid structure; Animal Model; Antidiabetic Drugs; Apolipoprotein E; Astrocytosis; Attenuated; Autopsy; Behavior; Behavioral; Biochemical Markers; Biochemistry; Brain; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Controlled Study; Data; Development; Diabetes Mellitus; Disease; Drug usage; Elderly; Exposure to; Frontotemporal Lobar Degenerations; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Genotype; Glimepiride; Gliosis; Goals; Hippocampus (Brain); Human; Impaired cognition; Knockout Mice; Knowledge; Left; Life; Link; Modeling; Morbidity - disease rate; Mus; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Nicorandil; Oral; Paper; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Potassium Channel; Pre-Clinical Model; Preclinical Testing; Proteins; Public Health; Publishing; Regulation; Research; Risk; Series; Sulfonylurea Compounds; Testing; Therapeutic; Transgenic Mice; age related; base; behavioral study; clinically relevant; genome wide association study; genome-wide; hippocampal sclerosis; mouse model; neurobehavioral; novel; novel therapeutics; pre-clinical; preclinical study; protein TDP-43; protein function; public health relevance; risk variant; volunteer

 DESCRIPTION (provided by applicant): Diseases that mimic Alzheimer's disease (AD) are understudied causes of cognitive impairment in the elderly. Poor understanding of these diseases has hampered AD clinical trials while leaving important illnesses largely unaddressed from a clinical research perspective. A common and high-morbidity "AD mimic" is hippocampal sclerosis of aging (HS-Aging). HS-Aging is characterized by cell loss and astrocytosis in the hippocampus, with phosphorylated TDP-43 (P-TDP-43) pathology, not correlated with AD-type pathology, nor with APOE genotype. HS-Aging affects 10-25% of persons above age 85 years. The PI of the current proposal has studied HS-Aging extensively, including the first HS-Aging genome-wide association study (GWAS). A genetic polymorphism in the ABCC9 gene is linked to HS-Aging pathology. Importantly, we recently (Jan 2015) published a paper that replicated this observation in a separate group of research volunteers. The ABCC9 mutation enables us to address a central as-yet unrealized promise of genomics studies: clinical relevance. Remarkably, the GWAS-identified HS-Aging risk gene ABCC9 is a "druggable target"-both agonist and antagonist drugs are used widely in humans. In a prior published study, we found that exposure to sulfonylureas (oral anti-diabetic drugs that antagonize ABCC9 protein function) is associated with increased risk for HS-Aging pathology in humans, controlling for other factors. We need to assess the potential to target ABCC9 in a preclinical model for more rigorous control of experimental parameters. That will enable us to test the impact of an ABCC9 agonist drug, with the opposite effects of sulfonylureas, as a potential therapy for clinical HS-Aging. Overall Hypothesis: Pharmacologic ABCC9 regulation provides a therapeutic strategy for HS-Aging. We propose proof-of-concept preclinical studies to test the specific hypothesis that ABCC9 agonist nicorandil attenuates pathologic and behavioral features of HS-Aging in a mouse model. Specific Aims: 1. Characterize the first preclinical model of HS-Aging. In GRN knockout (GRN-KO) mice, our studies indicate the presence of brain changes that model features of human HS-Aging, including hippocampal P-TDP-43 pathology and hippocampus-related neurobehavioral deficits. 2. Based on studies in humans, test in the GRN-KO mouse model the hypothesis that a sulfonylurea drug (glimepiride) which antagonizes ABCC9, exacerbates HS-Aging pathology and abnormal behavior. 3. Test in the GRN-KO mouse model the hypothesis that nicorandil, which opens the potassium channel (the opposite activity as sulfonylureas), reduces HS-Aging-related abnormal pathology and behavior. Since there are similar pathologies and genetic susceptibilities, the therapeutic strategy may also be relevant to a separate lethal neurodegenerative disease, frontotemporal lobar degeneration (FTLD).

 描述(申请人提供)：类似阿尔茨海默病(AD)的疾病是导致老年人认知障碍的未被充分研究的原因。对这些疾病缺乏了解阻碍了AD的临床试验，同时从临床研究的角度来看，重要的疾病基本上没有得到解决。一种常见且发病率较高的“模拟AD”是衰老的海马区硬化(HS-Aging)。HS-Aging的特点是海马区细胞丢失和星形胶质细胞增多，具有磷酸化TDP-43(P-TDP-43)病理，与AD类型的病理无关，也与APOE基因型无关。85岁以上人群中有10%-25%的人会受到HS-Aging的影响。目前提案的PI对HS-Aging进行了广泛的研究，包括第一个HS-Aging全基因组关联研究(GWAS)。ABCC9基因的遗传多态与HS-Aging病理有关。重要的是，我们最近(2015年1月)发表了一篇论文，在另一组研究志愿者中重复了这一观察结果。ABCC9突变使我们能够解决基因组学研究中尚未实现的一个核心承诺：临床相关性。值得注意的是，GWAS确认的HS-Aging风险基因ABCC9是一个“可用药的靶点”--激动剂和拮抗剂药物在人类中都广泛使用。在之前发表的一项研究中，我们发现，在控制其他因素的情况下，暴露于磺脲类药物(拮抗ABCC9蛋白功能的口服抗糖尿病药物)与人类HS-Aging病理的风险增加相关。我们需要评估在临床前模型中靶向ABCC9的可能性，以便更严格地控制实验参数。这将使我们能够测试ABCC9激动剂药物的影响，与磺脲类药物的作用相反，作为临床HS-Aging的潜在治疗方法。总体假设：ABCC9的药理学调节为HS-Aging提供了一种治疗策略。我们建议进行概念验证临床前研究，以检验ABCC9激动剂尼可地尔在小鼠模型中减轻HS-Aging的病理和行为特征这一特定假设。具体目标：1.首次建立HS-Aging的临床前模型。在GRN基因敲除(GRN-KO)小鼠中，我们的研究表明存在模拟人类HS-衰老特征的脑变化，包括海马区P-TDP-43病理和海马区相关神经行为缺陷。2.在人类研究的基础上，在GRN-KO小鼠模型上验证以下假设：磺脲类药物(格列美脲)拮抗ABCC9，加剧HS-衰老的病理和异常行为。3.在GRN-KO小鼠模型中测试尼可地尔开放钾通道(与磺脲类药物的活性相反)，减少HS-衰老相关的异常病理和行为的假说。由于存在相似的病理和遗传易感性，治疗策略可能也与另一种致命的神经退行性疾病-额颞叶变性(FTLD)有关。