Targeting Rho Kinases for Alzheimer's disease Therapeutics

靶向 Rho 激酶治疗阿尔茨海默病

基本信息

批准号：
9919492
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
项目类别：
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/9919492
关键词：
Abeta synthesis Address Affect Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy American Amyloid Amyloid beta-Protein Autophagocytosis Behavior Behavioral Biochemical Biological Availability Biological Markers Blood Pressure Brain 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 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 conditional knockout density drug development effective therapy entorhinal cortex human disease improved inhibitor/antagonist innovation kinase inhibitor mild cognitive impairment mouse model novel prevent protein aggregation protein kinase inhibitor proteostasis rho rho GTP-Binding Proteins side effect tau Proteins tau mutation therapeutic target therapy development three-dimensional modeling

项目摘要

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.

项目概要目前的阿尔茨海默病 (AD) 疗法主要集中于淀粉样蛋白 - β (Aβ) 肽，但生物标志物研究表明，Aβ 的作用可能在临床症状出现之前达到最大，突触损失和微管相关蛋白 tau 的细胞内积累与认知能力下降，但目前很少有治疗策略针对这些机制。抑制剂用于治疗人类疾病，其中有两种是泛 Rho 相关蛋白激酶 (ROCK) 1 和 2 抑制剂在 2000 年代中期，ROCK 被确定为假定的翻译靶点。然而，由于三个关键障碍，这一令人兴奋的途径的进展陷入停滞：1）除了与 Aβ 生成相关的机制之外，ROCK 与 AD 发病机制之间缺乏联系，2) 缺乏遗传模型来测试 ROCK1 或 ROCK2 在 AD 小鼠中的作用，以及 3) 缺乏激酶抑制剂我们的目标是通过新的数据链接来克服这些障碍。 AD 进展中 ROCK 的结构可塑性变化以及采用新的 ROCK1 和 ROCK2 条件基因敲除小鼠以及新型全选择性 ROCK 抑制剂和异构体选择性 ROCK 抑制剂，具有高生物利用度在目标 1 中，我们将讨论 ROCK1 和 ROCK2 的贡献。在目标 2 中，我们将测试长期 ROCK 抑制对 Aβ 诱导的树突结构退化的影响。 AD 小鼠模型，在目标 3 中，我们将阐明 ROCK1 和 ROCK2 介导的机制 Tau 蛋白稳态和自噬诱导。