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 当前的阿尔茨海默氏病（AD）疗法主要关注淀粉样蛋白β（Aβ）肽，但生物标志物 研究表明，在临床症状发作之前，Aβ效应可能是最大的。 Aβ下游， 微管相关蛋白tau的突触丧失和细胞内积累与与 认知能力下降，但几乎没有治疗策略以这些机制为目标。目前，二十九个激酶 抑制剂用于治疗人类疾病，其中两种是泛Rho相关的蛋白激酶 （岩石）1和2抑制剂。在2000年代中期，岩石被确定为推定的翻译目标 遏制Aβ产生。但是，由于三个关键障碍，这一令人兴奋的途径的进展：1） 除了与Aβ世代相关的机制之外，岩石与AD发病机理之间缺乏联系，2） 缺乏测试AD小鼠Rock1或Rock2的作用的遗传模型，以及3）缺乏激酶抑制剂 提供高岩石选择性和大脑渗透率。我们的目标是通过新数据链接克服这些障碍 岩石到结构可塑性的变化广告进展并采用新的岩石和岩石2条件 敲除小鼠以及新型的泛和异工选择性岩石抑制剂，暴露了高生物利用度和 脑部渗透性无副作用。在AIM 1中，我们将解决Rock1和Rock2的贡献 到Aβ诱导的树突结构变性。在AIM 2中，我们将测试慢性岩石抑制作用 AD的鼠标模型，以及在AIM 3中，我们将阐明Rock1和Rock2介导的机制 tau蛋白质稳态和自噬诱导。