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.

摘要 阿尔茨海默病（AD）是世界上最常见的痴呆类型，也是阿尔茨海默病的主要原因之一。 死亡目前没有FDA批准的用于AD患者的药物可以显著改善疾病症状 或者是治愈性的。自噬调节剂正在成为AD的有希望的治疗方法。报告使用 AD相关蛋白如Aβ、Aβ前体蛋白（APP）、早老素1（Presenilin 1）功能障碍的小鼠模型 (PS1)和tau蛋白的研究表明，促进自噬可以减轻AD症状，包括改善认知功能， 海马体功能障碍和蛋白质聚集减少。然而，问题仍然存在， 靶向调节自噬的酶如激酶的临床相关药理学试剂，以及 对AD缺乏疗效。此外，AD中自噬的研究受到以下需要的阻碍： 描述易于评估自噬调节在细胞周期中的作用的信号通路， 疾病进展。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，以前没有在AD中进行过评价。我们的数据显示， 在人AD患者样品的脑中下调。我们的研究结果还表明，HUNK表达 与年龄匹配的未患病小鼠相比，5XFAD小鼠的海马中的细胞凋亡减少。认知 AD患者的缺陷包括主要由背侧海马介导的空间记忆和空间记忆的损伤， （dHip），以及情绪和动机行为，其主要由腹侧海马体（vHip）调节。 自噬与这些认知缺陷有关。此外，我们最近发现了一种药理学 诱导HUNK酶活性的试剂。从药理学的角度来看，HUNK的调节是 因为无论是转基因过表达Hunk的小鼠，还是具有生殖细胞的小鼠， 缺失的Hunk具有任何显著的发育或疾病相关缺陷。因此， 增加HUNK活性可用于改善AD的治疗。我们这些研究的目的是 HUNK的激活及其对AD相关病理学和认知功能障碍的后续影响。这些 研究将使我们能够确定HUNK是否是干预AD的药物靶点。到目前为止，汉克 尚未在大脑中进行广泛研究，我们建议测试一种新的HUNK药理学试剂 应用于AD，使这些研究具有高度创新性。这项资助的首要假设是， HUNK在AD脑的腹侧（v）髋和背侧（d）髋中下降，导致AD病理学和神经功能障碍。 空间记忆和动机行为。假设诱导HUNK活性的方法可以逆转 AD相关的功能障碍和认知能力下降。