Enhancing Cognitive Resilience In Parkinson's Disease: Role Of Antiaging Protein Klotho

增强帕金森病的认知弹性：抗衰老蛋白 Klotho 的作用

• 批准号: 10525864
• 负责人: Nijee Luthra
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525864
• 关键词: Adherence; Adult; Age; Aging; Alleles; Amyloid; Amyloid beta-Protein; Animal Model; Attenuated; Awareness; Biological Markers; Biostatistical Methods; Blood; Brain; Clinical; Clinical Investigator; Clinical Trials; Cognition; Cognitive; Complement; Conduct Clinical Trials; Control Groups; Critiques; Databases; Dementia; Denervation; Deterioration; Development; Disease; Exercise; Goals; Growth; Health; Home; Hormones; Impaired cognition; Impairment; Letters; Life; Light; Link; Longevity; Measures; Mediating; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Movement Disorders; Nerve Degeneration; Neurologist; Outcome; Parkinson Disease; Participant; Pathogenicity; Pathology; Pathway interactions; Patient Outcomes Assessments; Patients; Persons; Phenotype; Physical Exercise; Physical Performance; Pilot Projects; Population; Proteins; Quality of life; Randomized; Randomized Controlled Trials; Research; Research Personnel; Research Proposals; Research Training; Role; Serum; Signal Transduction; Statistical Methods; Supervision; Synaptic plasticity; Testing; Training; Training Programs; age effect; alpha synuclein; anti aging; base; brain volume; career; career development; cognitive ability; cognitive enhancement; cognitive function; cognitive impairment in Parkinson' s; cognitive testing; cohort; cost; data harmonization; design; effective therapy; executive function; exercise intervention; experience; genetic variant; healthy aging; improved; innovation; klotho protein; longitudinal analysis; mouse model; multimodality; neurofilament; novel; novel therapeutic intervention; novel therapeutics; overexpression; pandemic disease; progression marker; relating to nervous system; research and development; resilience; response; single photon emission computed tomography; strength training; tau Proteins; treatment strategy

PROJECT SUMMARY This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) by Dr. Nijee Luthra, a neurologist specializing in movement disorders. As the number of people with Parkinson’s disease (PD) is expected to grow to pandemic proportions, cognitive deterioration associated with PD will prevail in a majority of this population. The integrated career development and research plan proposed for this K23 award is motivated by an increasing awareness of the urgent need to identify pathways that target cognitive impairment in PD. Exercise has potent anti-aging effects and can influence cognitive outcomes in PD but its underlying mechanisms remain unclear. Identifying biomarkers that respond to exercise, and how they associate with cognition and underlying disease pathology may elucidate key mechanisms for countering cognitive decline. This proposal focuses on longevity hormone klotho as a biomarker that may mediate exercise-induced benefits and contribute to cognitive resilience. Klotho has been shown to enhance cognition, synaptic plasticity, and brain volumes in mouse models of aging and neurodegeneration. Dr. Luthra and her team have also recently shown that klotho associates with better cognitive function in PD patients. While klotho levels decrease with aging and in PD, physical exercise robustly increases klotho levels in healthy adults. Whether exercise increases klotho in PD and protects against cognitive decline is not yet known. To this end, the aims of this research proposal are: 1) knowing its positive link with cognition, to now investigate whether klotho modifies underlying markers of PD pathology, and 2) in parallel, design a pilot study to determine if klotho increases in response to exercise in PD and correlates with improved cognitive abilities. Answers to these questions would highlight the potential of klotho as an exercise-related biomarker and as a new pathway for targeting cognitive dysfunction. The research plan is complemented by didactic and practical training in design and conduct of clinical trials, advanced biostatistical methods, and analysis and interpretation of multimodal biomarkers and cognitive assessments. To accomplish the goals of this research and training, the candidate has assembled a mentoring team with decades of experience in clinical trials and exercise interventions, along with expertise in biomarkers and cognitive impairment in PD. Completion of this research plan and training objectives will allow the candidate to advance her career in becoming an independent clinical investigator focused on investigating strategies such as exercise and multiple related biomarkers that mediate cognitive resilience in PD.

项目概要 这是申请由 Dr. 指导的以患者为导向的研究职业发展奖 (K23)。 Nijee Luthra，一位专门研究运动障碍的神经科医生。 疾病（PD）预计将发展到大流行的程度，与 PD 相关的认知功能恶化将 为此提出的综合职业发展和研究计划受到大多数人的欢迎。 K23 奖项的动机是人们越来越认识到迫切需要确定针对目标的途径 帕金森病中的认知障碍。运动具有有效的抗衰老作用，并能影响帕金森病的认知结果。 但其潜在机制仍不清楚，识别对运动有反应的生物标志物以及它们如何发挥作用。 与认知和潜在疾病病理学相关可能阐明对抗的关键机制 该提案重点关注长寿激素 klotho 作为可能介导的生物标志物。 Klotho 已被证明可以增强认知能力， Luthra 博士和她的小鼠衰老和神经退行性疾病模型中的突触可塑性和脑容量。 研究小组最近还表明，klotho 与 PD 患者更好的认知功能相关。 随着年龄的增长，klotho 水平会降低，而在帕金森病中，体育锻炼会显着增加健康成年人的 klotho 水平。 运动是否会增加帕金森病的克洛索并防止认知能力下降目前尚不清楚。 本研究计划的目的是：1）了解其与认知的积极联系，现在调查是否 klotho 修改了 PD 病理学的潜在标志物，并且 2) 同时设计一项试点研究以确定是否 klotho 对 PD 运动的反应增加，并与认知能力的提高相关。 这些问题将凸显 klotho 作为运动相关生物标志物和新途径的潜力 针对认知功能障碍。 该研究计划还辅以临床设计和实施方面的教学和实践培训。 试验、先进的生物统计学方法以及多模式生物标志物和认知的分析和解释 为了实现本研究和培训的目标，候选人组织了一个指导。 团队在临床试验和运动干预方面拥有数十年的经验，以及生物标志物方面的专业知识 完成本研究计划和培训目标将使 候选人推动她的职业生涯，成为一名专注于调查的独立临床研究者 运动和多种相关生物标志物等调节帕金森病认知弹性的策略。