Novel Kinase Target in Alzheimer's Disease

阿尔茨海默病的新激酶靶点

• 批准号: 10808473
• 负责人: Yao-Ying Ma
• 金额: $ 43.32万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10808473
• 关键词: Acute; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid beta-Protein; Autophagocytosis; Behavior; Behavioral; Binding; Brain; Brain region; Cause of Death; Cell Survival; Cognition; Cognitive deficits; Collaborations; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Dementia; Development; Disease; Disease Progression; Dorsal; Drug Targeting; Engineering; Enzymes; FDA approved; Functional disorder; Goals; Grant; Hip region structure; Hippocampus; Human; Impaired cognition; Impairment; Indiana; Intervention; Learning; Link; Mediating; Memory; Methods; Molecular; Motivation; Mus; NOR Mouse; Outcome; Pathologic; Pathology; Pharmaceutical Preparations; Pharmacology Study; Phospho-Specific Antibodies; Phosphorylation; Phosphotransferases; Protein Precursors; Proteins; Reagent; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Symptoms; System; Testing; Universities; behavior test; cellular pathology; clinical application; clinically relevant; developmental disease; digital; druggable target; emotional behavior; improved; innovation; member; motivated behavior; mouse model; novel; overexpression; pharmacologic; presenilin-1; protein aggregation; protein expression; spatial memory; targeted agent; tau Proteins

ABSTRACT Alzheimer’s disease (AD) is the most common type of dementia in the world and one of the main causes of death. There are currently no FDA approved drugs for AD patients that significantly improve disease symptoms or are curative. Autophagy modulating agents are emerging as promising therapies for AD. Reports using mouse models with dysfunction of AD-associated proteins such as Aβ, Aβ precursor protein (APP), presenilin 1 (PS1), and tau, show that promoting autophagy alleviates AD symptoms including improvement of cognitive dysfunction in the hippocampus and a reduction in protein aggregation. However, a problem persists where clinically relevant pharmacological agents to target enzymes that regulate autophagy, such as kinases, and have efficacy toward AD are lacking. Furthermore, the study of autophagy in AD is hampered by the need to delineate the signaling pathways that are tractable to evaluate the effect of autophagy modulation during disease progression. We propose to address these problems by studying a protein kinase called HUNK that is an autophagy promoting factor and has not been previously evaluated in AD. Our data shows that HUNK is downregulated in the hippocampi of human AD patient samples. Our findings also show that HUNK expression in the hippocampus of 5XFAD mice is reduced compared to age-matched non-diseased mice. Cognition deficits in AD patients include impairments in both spatial memory, primarily mediated by dorsal hippocampus (dHip), and emotional and motivated behaviors, which are primarily regulated by ventral hippocampus (vHip). Autophagy is linked to these cognitive deficits. Furthermore, we have recently identified a pharmacological agent that induces HUNK enzymatic activity. From a pharmacological perspective, modulation of HUNK is promising because neither mice engineered to transgenically overexpress Hunk nor mice with germline deletion of Hunk have any significant developmental or disease related defects. Consequently, methods to increase HUNK activity could be applied to improve treatment of AD. Our goal with these studies is to test activation of HUNK and its subsequent effect on AD-related pathology and cognitive dysfunction. These studies will allow us to determine whether HUNK is a druggable target for intervention in AD. Until now, HUNK has not been studied extensively in brain, and we are proposing to test a novel HUNK pharmacological agent for application to AD, making these studies highly innovative. The overarching hypothesis of this grant is that HUNK declines in ventral (v) Hip and dorsal (d) Hip of AD brains, leading to AD pathology and impairments in both spatial memory and motivation behaviors. Methods to induce HUNK activity are hypothesized to reverse AD-associated dysfunction and cognitive decline.

抽象的 阿尔茨海默氏病（AD）是世界上最常见的痴呆症类型，也是导致痴呆症的主要原因之一 目前 FDA 还没有批准用于 AD 患者的药物能够显着改善疾病症状。 自噬调节剂正在成为治疗 AD 的有希望的疗法。 AD 相关蛋白（如 Aβ、Aβ 前体蛋白 (APP)、早老素 1）功能障碍的小鼠模型 (PS1) 和 tau 蛋白表明，促进自噬可减轻 AD 症状，包括改善认知能力 海马体功能障碍和蛋白质聚集减少然而，问题仍然存在。 临床相关的药物制剂，以调节自噬的酶为目标，例如激酶，以及 此外，自噬在 AD 中的研究也因需要而受到阻碍。 描绘了易于评估自噬调节作用的信号通路 我们建议通过研究一种名为 HUNK 的蛋白激酶来解决这些问题。 一种自噬促进因子，之前尚未在 AD 中进行过评估。我们的数据表明 HUNK 是一种自噬促进因子。 我们的研究结果还表明，HUNK 在人类 AD 患者样本的海马中表达下调。 与年龄匹配的未患病小鼠相比，5XFAD 小鼠海马体的认知能力有所降低。 AD 患者的缺陷包括空间记忆受损，主要由背侧海马介导 (dHip) 以及情绪和动机行为，主要由腹侧海马体 (vHip) 调节。 自噬与这些认知缺陷有关，而且我们最近发现了一种药理学作用。 从药理学角度来看，HUNK 的调节是诱导 HUNK 酶活性的物质。 前景广阔，因为既没有转基因小鼠过度表达 Hunk，也没有带有种系的小鼠 删除 Hunk 有任何显着的发育或疾病相关缺陷的测试方法。 增加 HUNK 活性可用于改善 AD 的治疗。我们这些研究的目的是测试。 HUNK 的激活及其对 AD 相关病理和认知功能障碍的后续影响。 研究将使我们能够确定 HUNK 是否是 AD 干预的药物靶标。 尚未在大脑中进行广泛研究，我们建议测试一种新型 HUNK 药物制剂 应用于AD，使这些研究具有高度创新性。这项资助的总体假设是： AD 大脑的腹侧 (v) 髋部和背侧 (d) 髋部 HUNK 下降，导致 AD 病理学和损伤 诱导 HUNK 活动的方法被捕获以逆转。 AD 相关功能障碍和认知能力下降。