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.

项目摘要 这是Dr. Nijee Luthra，专门研究运动障碍的神经科医生。作为帕金森氏症的人数 疾病（PD）预计将成长为大流行比例，与PD相关的认知定义将 在大多数人群中占上风。为此提出的综合职业发展和研究计划 K23奖是出于越来越多的迫切需求确定目标的途径的动机 PD的认知障碍。运动具有潜在的抗衰老作用，可以影响PD的认知结果 但是它的基本机制尚不清楚。识别对运动反应的生物标志物以及如何 与认知和潜在疾病病理学联系在一起可能会阐明反对的关键机制 认知能力下降。该提议重点是长寿同性人Klotho作为一种可能调解的生物标志物 运动引起的好处并有助于认知弹性。 klotho已被证明可以增强认知， 衰老和神经退行性的小鼠模型中的突触可塑性和脑体积。卢斯拉博士和她 团队最近还表明，Klotho在PD患者中具有更好的认知功能。而克洛托 随着衰老和PD的降低，体育锻炼可强大地增加健康成年人的Klotho水平。 尚不清楚运动在PD中增加Klotho并预防认知能力下降。为此， 该研究建议的目的是：1）知道其与认知的积极联系，现在调查是否是否 Klotho修改了PD病理的潜在标记，2）并行设计了一项试点研究，以确定是否是否 Klotho响应PD的运动而增加，并与提高的认知能力相关。答案 这些问题将突出克洛索（Klotho）作为与运动有关的生物标志物的潜力和新的途径 用于靶向认知功能障碍。 该研究计划是通过在临床设计和行为方面的教学和实践培训完成的 试验，高级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 评估。为了实现这项研究和培训的目标，候选人汇集了一个心理 在临床试验和运动干预方面拥有数十年经验的团队，以及生物标志物的专业知识 和PD的认知障碍。完成本研究计划和培训目标将允许 候选人促进自己的职业生涯，成为一名专注于调查的独立临床研究者 诸如运动和多种相关的生物标志物等策略介导PD中的认知弹性。