权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10663859
负责人：
Vedad Delic
金额：
--
依托单位：
VA NEW JERSEY HEALTH CARE SYSTEM
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

来源：
https://reporter.nih.gov/project-details/10663859
关键词：
Acceleration Affect Animal Disease Models Animals Appearance Area Autophagocytosis Behavioral Biological Brain Brain Injuries Brain region Clinic Clinical Clinical Trials Deterioration Development Diagnosis Disease Progression Disease model Dizziness Effectiveness Equilibrium Event Exercise Exercise Test Experimental Designs Fiber Frequencies Future Gait Head Headache Health Healthcare Systems Histologic Histopathology Human Idiopathic Parkinson Disease Impairment In Vitro Inflammation Injections Injury K-Series Research Career Programs Knock-out LRRK2 gene Length of Stay Lesion Lewy Bodies Life Link Measures Metabolic Methods Mitochondria Modeling Modernization Molecular Morbidity - disease rate Mutation Nature Nausea Nerve Degeneration Nerve Growth Factor Receptors Neurodegenerative Disorders Neurotoxins New Jersey Outcome Measure Parkinson Disease Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Phenotype Phosphotransferases Physical therapy Populations at Risk Pre-Clinical Model Prevention Protein Family Proteins Protocols documentation Rattus Recovery Rehabilitation therapy Reporting Rest Tremor Risk Risk Factors Rodent Skull Fractures Substantia nigra structure Synapses TBI Patients Testing Therapeutic Time Training Translating Traumatic Brain Injury Unconscious State Veterans Vomiting Vulnerable Populations age related alpha synuclein combat combat zone dopaminergic neuron early onset environmental enrichment for laboratory animals executive function gain of function genome wide association study high risk improved in vivo inhibitor locomotor deficit middle age mild cognitive impairment mild traumatic brain injury mortality mutant neuroinflammation neuropathology neurophysiology neuroprotection neurotrophic factor non-genetic older patient oxidative damage palliative pars compacta pharmacologic preclinical study prevent progressive neurodegeneration sedentary trafficking treatment strategy white matter

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）导致帕金森病（PD）的风险增加56%。老兵PD在临床上表现为静止性震颤、平衡问题、步态不稳和运动缺陷。 PD的组织学标志是α-突触核蛋白（α-syn）病理通过相互连接的大脑扩散区域，和选择性损失的多巴胺能神经元在黑质pars延髓（SNpc）。没有治愈PD和治疗只能治标不治本。随着OEF/OIF退伍军人进入中年，当诊断出随着PD的发病率越来越高，重要的是要确定增加潜在风险的因素和事件。发展PD，更重要的是，减缓其进展的潜在缓解因素。运动已被显示可防止与年龄相关的大脑退化，并与更好的白色纤维完整性相关从而改善轻度认知障碍患者的执行功能。环境富集在动物和康复（包括患者的物理治疗）中，已被证明显着改善减少TBI患者的住院时间。然而，运动在预防 mTBI康复期间的PD未知。全基因组关联研究将突变与富含亮氨酸重复激酶-2导致病理学上无法与特发性PD区分的迟发性PD。这些研究结果表明，LRRK 2可能也在PD的非遗传原因中发挥作用。最近的体外和体内研究研究表明，抑制WT-LRRK 2或功能获得性LRRK 2突变体中的激酶活性，在神经炎症和PD模型中的神经保护。到目前为止，所有针对预防或阻止PD进展在人类临床试验中失败，这可能是由于临床前这些研究主要依赖于不完整的PD动物模型。尽管尽了最大努力，但使用这些不完整的 PD模型（例如，在PD中受影响的脑区中神经毒素诱导的病变，而不伴随α-syn 病理学）也未能在mTBI和PD之间产生真正的生物学联系。这种不明确性是这可能是为什么目前没有有效的康复方法或治疗来阻止或预防PD。注射致淀粉样蛋白生成的预形成α-syn纤维（PFF）进入啮齿动物的SNpc，导致人类- 像α-syn病理通过相互连接的大脑区域，进行性和选择性多巴胺能神经变性与PD相关的行为缺陷。使用这个更完整的迟发性PD模型，我们计划确定mTBI和PD之间的联系，并测试可能预防PD的潜在治疗方法。我们的总体假设是，重复性mTBI（r-mTBI）促进了脆弱个体（即，未检测到PD的患者），但运动结合新的药物治疗可以延缓PD的进展。 PD，即使在脆弱的人。我们将在PFF诱导的PD模型中检验我们的假设，运动沿着LRRK 2的药理学抑制可以预防PD。使用高度特异性LRRK 2抑制剂进入人体试验治疗诊断的PD，这是至关重要的，以确定是否与运动，这类可以预防高危人群中的PD。除了支持科学目标，这项事业发展奖将为Delic博士提供不同模型的脑损伤和行为训练，以及VA新泽西卫生保健系统的神经生理学结果测量。本次培训将使Delic博士能够成功地将这种和未来的治疗方法应用于临床。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson's-like pathology burden.

DOI：
10.1186/s40478-022-01475-9
发表时间：
2022-11-26
期刊：
Acta neuropathologica communications
影响因子：
7.1
作者：
通讯作者：

Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes.

DOI：
10.1007/s12035-021-02428-4
发表时间：
2021-09
期刊：
Molecular neurobiology
影响因子：
5.1
作者：
Zimering MB;Delic V;Citron BA
通讯作者：
Citron BA

Pyridostigmine bromide, chlorpyrifos, and DEET combined Gulf War exposure insult depresses mitochondrial function in neuroblastoma cells.

DOI：
10.1002/jbt.22913
发表时间：
2021-12
期刊：
Journal of biochemical and molecular toxicology
影响因子：
3.6
作者：
Delic V;Karp J;Klein J;Stalnaker KJ;Murray KE;Ratliff WA;Myers CE;Beck KD;Citron BA
通讯作者：
Citron BA

Acute gene expression changes in the mouse hippocampus following a combined Gulf War toxicant exposure.