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症类型，也是导致痴呆的主要原因之一 死亡。目前还没有FDA批准的用于AD患者的显著改善疾病症状的药物 或者是可以治愈的。自噬调节剂正在成为治疗AD的有前途的药物。报告使用 Aβ、Aβ前体蛋白(APP)、早老素1等AD相关蛋白功能障碍的小鼠模型 (PS1)和tau表明，促进自噬可以缓解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，问题仍然存在于以下位置 临床上相关的药理学药物，靶向调节自噬的酶，如激酶和 对阿尔茨海默病缺乏疗效。此外，自噬在AD中的研究由于需要 描述易于处理的信号通路，以评估自噬调节在 疾病的发展。我们建议通过研究一种名为BUNK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中进行过评估。我们的数据显示，帅哥 在人类AD患者样本的海马区下调。我们的研究结果还表明，帅气的表情 与年龄匹配的未患病小鼠相比，5XFAD小鼠海马区的表达减少。认知 阿尔茨海默病患者的空间记忆障碍主要由背侧海马区介导 (DHip)，以及情绪和动机行为，这些行为主要由腹侧海马区(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 诱导大块酶活性的试剂。从药理学的角度来看，对大块头的调节 前景看好，因为无论是转基因小鼠还是生殖系小鼠都不能过表达BUNK 大块头缺失有任何明显的发育或疾病相关缺陷。因此，方法是 增加BUCK活性可用于改善AD的治疗。我们进行这些研究的目的是为了测试 BUNK的激活及其在AD相关病理和认知功能障碍中的后续作用。这些 研究将使我们能够确定BUNK是否是干预AD的药物靶点。到现在为止，帅哥 在大脑中还没有得到广泛的研究，我们正在提议测试一种新的BUCK药理制剂 对于AD的应用，使这些研究具有很强的创新性。这笔赠款的首要假设是 阿尔茨海默病患者大脑腹侧(V)髋部和背侧(D)髋部大块减少，导致AD病理和脑损伤。 空间记忆和动机行为。诱导大块头活动的方法被假设为逆转 与AD相关的功能障碍和认知能力下降。