Exercise and pharmacological LRRK2 inhibition for preventing PD

运动和药理 LRRK2 抑制可预防 PD

基本信息

  • 批准号:
    10454795
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Mild Traumatic Brain Injury (mTBI) results in a 56% higher risk of developing Parkinson’s disease (PD) in U.S. Veterans. PD presents clinically with resting tremors, balance problems, gait instability, and locomotor deficits. Histological hallmarks of PD are spread of alpha synuclein (α-syn) pathology through interconnected brain regions, and selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). There is no cure for PD and treatments are only palliative. With OEF/OIF Veterans entering middle-age, when the diagnosis of PD becomes more prevalent, it is important to identify factors and events that increase the risk of potentially developing PD and, more importantly, potential mitigating factors that slow its progression. Exercise has been shown to prevent age-related brain deterioration and is associated with better white matter fiber integrity resulting in improved executive function in patients with mild cognitive impairment. Environmental enrichment in animals and rehabilitation including physiotherapy in patients, have been shown to significantly improve recovery and decrease hospital stay in patients with TBI. However, the effectiveness of exercise at preventing PD during rehabilitation from mTBI is unknown. Genome wide association studies have linked mutations in Leucine Rich Repeat Kinase-2 to late onset PD that is pathologically indistinguishable from idiopathic PD. These findings suggest that LRRK2 likely also plays a role in non-genetic causes of PD. Recent in vitro and in vivo studies show that inhibition of kinase activity in WT-LRRK2 or gain-of-function LRRK2 mutants, confers robust neuroprotection in models of neuroinflammation and PD. To date, all pharmacological treatments aimed at preventing or stopping PD progression have failed in human clinical trials and this may be due to preclinical studies that relied primarily on incomplete PD animal models. In spite of best efforts, use of these incomplete PD models, (e.g. neurotoxin induced lesions in brain areas affected in PD without accompanying α-syn pathology) has also failed to produce a bonafide biological link between mTBI and PD. This lack of clarity is likely why no effective rehabilitation methods or treatments to stop or prevent PD currently exist. Injection of amyloidogenic pre-formed α-syn fibrils (PFF) into the SNpc of rodents causes formation and spread of human- like α-syn pathology through the interconnected brain regions, progressive and selective dopaminergic neurodegeneration with PD related behavioral deficits. Using this more complete model of late onset PD, we plan to determine the connection between mTBI and PD and to test potential treatments that may prevent PD. Our overall hypothesis is that repetitive mTBI (r-mTBI) promotes PD pathology in vulnerable individuals (i.e. those with undetected PD), but exercise combined with new pharmacotherapies can delay the progression of PD, even in vulnerable individuals. We will test our hypothesis in the PFF induced model of PD and test if exercise along with pharmacological inhibition of LRRK2 can prevent PD. With highly specific LRRK2 inhibitors entering human trials for treating diagnosed PD, it is essential to determine if together with exercise, this class of drugs can prevent PD in at risk populations. In addition to supporting the scientific objectives, this career development award will provide Dr. Delic with training in different models of brain injury and behavioral as well as neurophysiological outcome measures at the VA New Jersey Health Care System. This training will enable Dr. Delic to successfully translate this and future treatments to the clinic.
在美国,轻度创伤性脑损伤(MTBI)导致患帕金森病(PD)的风险增加56%。 退伍军人。帕金森病的临床表现为静止性震颤、平衡问题、步态不稳定和运动障碍。 帕金森病的组织学特征是α-突触核蛋白(α-SYN)病理通过相互连接的大脑传播 黑质致密部多巴胺能神经元的选择性丢失。没有 帕金森病的治愈和治疗只是治标不治本。随着OEF/OIF退伍军人进入中年,当诊断 帕金森病变得更加普遍,重要的是找出增加潜在风险的因素和事件 发展中的帕金森病,更重要的是,潜在的缓解因素,减缓其进展。一直以来,锻炼 被证明可以防止与年龄相关的大脑退化,并与更好的白质纤维完整性有关 从而改善轻度认知障碍患者的执行功能。环境浓缩 在动物和康复方面,包括对患者进行物理治疗,已经被证明有显著的改善 促进颅脑损伤患者的康复,减少住院时间。然而,运动在预防 重型颅脑损伤康复期间的帕金森病尚不清楚。全基因组关联研究已经将突变与 富含亮氨酸的重复蛋白-2至迟发性帕金森病,在病理上与特发性帕金森病无法区分。这些 研究结果表明,LRRK2可能也在帕金森病的非遗传原因中发挥作用。最新的体外和体内实验 研究表明,抑制WT-LRRK2或功能增强型LRRK2突变体中的激酶活性,可以提供强大的 神经炎症和帕金森病模型的神经保护作用。到目前为止,所有的药物治疗旨在 在人类临床试验中,阻止或阻止帕金森病进展失败,这可能是由于临床前 主要依赖不完全帕金森病动物模型的研究。尽管尽了最大努力,但使用这些不完整的 帕金森病模型(例如,神经毒素在帕金森病患者受影响的脑区造成的损害,而不伴有α-SYN 病理学)也未能在mTBI和帕金森病之间产生真正的生物学联系。这种缺乏清晰度的现象 这可能是为什么目前没有有效的康复方法或治疗方法来阻止或预防帕金森病的原因。注射用 啮齿类动物SNPC中的淀粉样变性预成型α-syn纤维(PFF)可导致人类... 就像α-SYN病理一样,通过相互连接的脑区,进行性和选择性多巴胺能 伴有帕金森病相关行为缺陷的神经变性。使用这个更完整的迟发性帕金森病模型,我们 计划确定mTBI和帕金森病之间的联系,并测试可能预防帕金森病的潜在治疗方法。 我们的总体假设是,重复性mTBI(r-mTBI)促进了易感个体的帕金森病病理(即, 那些未被发现的帕金森病患者),但运动结合新的药物疗法可以延缓 PD,即使在脆弱的个体中也是如此。我们将在PFF诱导的PD模型中检验我们的假设,并检验是否 运动结合LRRK2的药物抑制可以预防帕金森病。使用高度特异的LRRK2抑制剂 进入治疗诊断为帕金森病的人体试验,确定是否与运动一起,这一类别是至关重要的 在高危人群中使用药物可以预防帕金森病。除了支持科学目标,这一职业 发展奖将为Delic博士提供不同脑损伤模型和行为AS的培训 以及退伍军人事务部新泽西医疗保健系统的神经生理结果测量。这次培训将 使Delic博士能够成功地将这种治疗方法和未来的治疗方法转化为临床治疗。

项目成果

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Vedad Delic其他文献

Vedad Delic的其他文献

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{{ truncateString('Vedad Delic', 18)}}的其他基金

Exercise and pharmacological LRRK2 inhibition for preventing PD
运动和药理 LRRK2 抑制可预防 PD
  • 批准号:
    10663859
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Exercise and pharmacological LRRK2 inhibition for preventing PD
运动和药理 LRRK2 抑制可预防 PD
  • 批准号:
    10178142
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:

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