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Fbw7 as a therapeutic target for treating Parkinson's disease

Fbw7作为治疗帕金森病的治疗靶点

基本信息

批准号：
9084633
负责人：
Steven I Reed
金额：
$ 41.96万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9084633
关键词：
Adverse effects Aging Apoptosis Apoptotic BCL2 gene Behavioral Binding Biological Assay Biological Availability Cell Death Cessation of life Characteristics Clinical Trials Collection Computer Simulation Coupled Disease Disease model Dissection Dose Etiology Exhibits FBXW7 gene Family member Gene Mutation Genes Genetic Models Goals Health Hour Human In Vitro Incidence Inherited Intoxication Lead Libraries Life Link Long-Term Effects Longevity Mediating Midbrain structure Modeling Molecular Motor Mus Mutate Nature Nerve Degeneration Nerve Fibers Neurons Oncogenes Oral PARK2 gene Parkinson Disease Pathology Penetrance Property RNA Interference Research Risk Role Sampling Staging Stress Substantia nigra structure Syndrome Technology Testing Therapeutic Time Ubiquitin Ubiquitin-mediated Proteolysis Pathway Veins Western Blotting Work acute toxicity cancer risk carcinogenesis cohort cost dopaminergic neuron drug discovery effective therapy in vivo inhibitor/antagonist motor disorder mouse model nanomolar neuromelanin neuron loss neuronal survival parkin gene/protein pars compacta pharmacokinetic characteristic prevent research study response screening small molecule small molecule inhibitor therapeutic target therapy development tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized by a spectrum of motor disorders that is caused be progressive death of dopaminergic neurons in a midbrain region known as the substantia nigra pars compacta (SNpc). Although 60,000 new cases of PD present in the US every year and an estimated 10 million people are living with the disease world-wide, there is no known effective treatment and the disease is invariably progressive. Although most PD is sporadic in nature, a significant cohort has been shown to be transmitted genetically. By investigating the genes and mutations that cause PD, it has been hoped that an understanding of the etiology and pathology of the disease at the molecular level will lead to effective therapies. In that vein, we have been engaged in research aimed at understanding the role of parkin, a ubiquitin ligase encoded by the most frequently mutated gene in recessive hereditary PD, PARK2. Our research has led to the conclusion that the neuroprotective effect of parkin is mediated, at least in part, by targeting the substrate binding adaptor of another ubiquitin ligase, SCFFbw7, for ubiquitin-mediated proteasomal degradation. We have also determined that the critical target of the SCFFbw7 ubiquitin ligase in this context is the pro-survival Bcl-2 family member Mcl-1, essential for neuronal survival. Using an in silico approach, we have identified small molecule inhibitors of SCFFbw7. All bind to Fbw7 and prevent it from forming productive interactions with Mcl-1 in primary neurons. Most importantly, these compounds protect primary neurons from various forms of stress-induced apoptosis at sub-nanomolar concentrations. Therefore, we are proposing to use one compound with good pharmacokinetic characteristics to determine whether Fbw7 is a valid therapeutic target in vivo using established mouse PD models. Should these experiments be successful, our ultimate goal is to arrive at Fbw7 inhibitors that have druglike characteristics so that they can be developed to the stage of entering human clinical trials.

描述（由申请人提供）：帕金森病（PD）的特征在于一系列运动障碍，这些运动障碍是由中脑区域（称为黑质黑部（SNpc））中多巴胺能神经元的进行性死亡引起的。尽管美国每年有60，000例PD新发病例，全球估计有1000万人患有这种疾病，但没有已知的有效治疗方法，而且这种疾病总是进行性的。虽然大多数PD在性质上是散发性的，但已显示出显著的队列是遗传性的。通过研究导致PD的基因和突变，人们希望在分子水平上了解疾病的病因和病理学将导致有效的治疗。在这方面，我们一直在从事旨在了解parkin的作用的研究，parkin是一种由隐性遗传性PD中最常突变的基因PARK 2编码的泛素连接酶。我们的研究得出结论，帕金的神经保护作用是介导的，至少部分是通过靶向另一种泛素连接酶SCFFbw 7的底物结合接头，用于泛素介导的蛋白酶体降解。我们还确定了SCFFbw 7泛素连接酶在这种情况下的关键目标是促生存Bcl-2家族成员Mcl-1，对神经元存活至关重要。使用计算机模拟方法，我们已经鉴定了SCFFbw 7的小分子抑制剂。所有这些都与Fbw 7结合，并阻止它与原代神经元中的Mcl-1形成有效的相互作用。最重要的是，这些化合物在亚纳摩尔浓度下保护原代神经元免受各种形式的应激诱导的细胞凋亡。因此，我们建议使用一种具有良好药代动力学特征的化合物，使用已建立的小鼠PD模型来确定Fbw 7是否是有效的体内治疗靶点。如果这些实验成功，我们的最终目标是获得具有药物样特征的Fbw 7抑制剂，以便它们可以发展到进入人体临床试验的阶段。