Targeting Rho Kinases for Alzheimer's disease Therapeutics

靶向 Rho 激酶治疗阿尔茨海默病

• 批准号: 9382081
• 负责人: Jeremy H. Herskowitz
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9382081
• 关键词: Abeta synthesis; Address; Adverse effects; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein; Autophagocytosis; Behavior; Behavioral; Biochemical; Biological Availability; Biological Markers; Blood Pressure; Brain; Brain Diseases; Chemistry; Chronic; Clinical; Data; Dementia; Dendritic Spines; Development; Disease; Disease Progression; Drosophila genus; Drug Targeting; Enzymes; Exhibits; FRAP1 gene; Generations; Genetic; Genetic Models; Goals; Histologic; Human; Image; Impaired cognition; Knockout Mice; Link; MAPT gene; Mediating; Monitor; Mus; Neurons; Organ; Outcome Measure; Pathogenesis; Pathway interactions; Penetrance; Pharmaceutical Preparations; Pharmacology; Population; Predisposition; Protein Isoforms; Protein Kinase; Protein Kinase Inhibitors; ROCK1 gene; Rho-associated kinase; Rodent; Role; Seizures; Serum; Signal Transduction; Structure; Symptoms; Synapses; Testing; Therapeutic; Thinness; Vertebral column; base; behavior test; beta amyloid pathology; density; disorder prevention; drug development; effective therapy; entorhinal cortex; human disease; improved; inhibitor/antagonist; innovation; kinase inhibitor; mild cognitive impairment; mouse model; novel; prevent; protein aggregate; protein kinase inhibitor; proteostasis; rho; rho GTP-Binding Proteins; tau Proteins; tau mutation; therapeutic target; therapy development; three-dimensional modeling

Project Summary Current Alzheimer's disease (AD) therapies predominantly focus on amyloid-β (Aβ) peptides, but biomarker studies indicate that Aβ effects may be maximal before onset of clinical symptoms. Downstream of Aβ, synapse loss and intracellular accumulation of the microtubule-associated protein tau correlate strongly with cognitive decline, yet few therapeutic strategies target these mechanisms. Presently, twenty-nine kinase inhibitors are used to treat human diseases, and out of these, two are pan- Rho-associated protein kinases (ROCK) 1 and 2 inhibitors. In the mid-2000s, the ROCKs were identified as putative translational targets to curb Aβ production. However, progress on this exciting avenue languished due to three critical barriers: 1) the lack of connection between ROCKs and AD pathogenesis beyond mechanisms tied to Aβ generation, 2) the lack of genetic models to test the role of ROCK1 or ROCK2 in AD mice, and 3) the lack of kinase inhibitors offering high ROCK-selectivity and brain penetrance. We aim to overcome these barriers with new data linking ROCKs to structural plasticity changes in AD progression and employing new ROCK1 and ROCK2 conditional knockout mice as well as novel pan- and isoform-selective ROCK inhibitors that exhibit high bioavailability and brain penetrance with no gross side-effects. In Aim 1, we will address the contribution of ROCK1 and ROCK2 to Aβ-induced dendritic structure degeneration. In Aim 2, we will test the effects of chronic ROCK inhibition in mouse models of AD, and in Aim 3, we will elucidate the mechanisms by which ROCK1 and ROCK2 mediate tau protein homeostasis and autophagy induction.

项目摘要 目前阿尔茨海默病（AD）的治疗主要集中在淀粉样蛋白-β（Aβ）肽，但生物标志物 研究表明，Aβ效应可能在临床症状出现之前达到最大。在Aβ下游， 突触丢失和微管相关蛋白tau的细胞内积累与 认知能力下降，但很少有治疗策略针对这些机制。目前，29种激酶 抑制剂用于治疗人类疾病，其中两种是泛Rho相关蛋白激酶 （ROCK）1和2抑制剂。在2000年代中期，ROCK被确定为推定的翻译靶点， 抑制Aβ生成。然而，由于三个关键障碍，这一令人兴奋的途径的进展停滞不前： ROCK与AD发病机制之间缺乏与Aβ生成相关机制以外的联系，2） 缺乏遗传模型来测试ROCK 1或ROCK 2在AD小鼠中的作用，以及3）缺乏激酶抑制剂 提供了高ROCK选择性和脑反射率。我们的目标是通过新的数据链接来克服这些障碍 ROCKs对AD进展中结构可塑性变化的影响以及采用新的ROCK 1和ROCK 2条件 敲除小鼠以及新型泛选择性和亚型选择性ROCK抑制剂，具有高生物利用度和 无明显副作用的大脑催眠在目标1中，我们将讨论ROCK 1和ROCK 2的贡献 Aβ诱导的树突状结构退化。在目标2中，我们将测试慢性ROCK抑制对小鼠的影响。 AD小鼠模型，在目的3中，我们将阐明ROCK 1和ROCK 2介导AD的机制。 tau蛋白稳态和自噬诱导。