Leveraging Proteomics to Understand the Link Between Chronic Kidney Disease and Cognitive Impairment

利用蛋白质组学了解慢性肾脏病与认知障碍之间的联系

• 批准号: 10684851
• 负责人: Lindsay M. Miller
• 金额: $ 12.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684851
• 关键词: Adhesions; Adult; Albumins; Albuminuria; Alzheimer' s disease related dementia; Biological; Biological Markers; Biometry; Blood Vessels; California; Cardiovascular Diseases; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Cognition; Cohort Studies; Collaborations; Complex; Creatinine; Cytokine Signaling; Data; Development; Diagnosis; Diagnostic; Discrimination; Disease; Doctor of Medicine; Doctor of Philosophy; Drug Targeting; Educational workshop; Elasticity; Elderly; End stage renal failure; Functional disorder; Glomerular Filtration Rate; Goals; Grant; Health; Heterogeneity; Hypertension; Immunity; Impaired cognition; Individual; Inflammation; Injury; Intervention; Intervention Trial; Investigation; Kidney; Kidney Diseases; Laboratories; Link; Medicine; Mentors; Mentorship; Methods; Monitor; Myocardial Infarction; Nature; Nephrology; Neuropsychology; Organ; Oxidative Stress; Participant; Pathology; Pathway interactions; Patients; Pattern; Persons; Plasma; Population; Protein Dynamics; Proteins; Proteome; Proteomics; Renal tubule structure; Research; Research Personnel; Risk; Risk Assessment; San Francisco; Sensitivity and Specificity; Symptoms; Technology; Testing; Time; Training; Troponin; Tubular formation; Universities; Urine; Work; Writing; biomarker panel; blood pressure intervention; body system; cardiovascular health; career; career development; clinical practice; clinical predictors; cognitive function; cohort; disease heterogeneity; high risk; insight; mild cognitive impairment; multidisciplinary; novel; novel strategies; novel therapeutics; pharmacologic; predictive panel; prevent; protein biomarkers; screening; skills; targeted biomarker; treatment response; urinary

PROJECT SUMMARY This is the initial submission of a K01 application by Lindsay Miller Ph.D., under the mentorship of Joachim Ix M.D., at the University of California, San Diego (UCSD). This proposal will establish Dr. Miller as an independent investigator and will leverage large-scale proteomics to understand the association and predictive ability of the proteome with cognitive impairment (CI), a clinical symptom of Alzheimer’s Disease and Related Dementias (ADRD) in older adults with chronic kidney disease (CKD). Candidate: Dr. Miller’s training objectives and career goals through this proposal include: 1) to become an expert in CKD and CI in older adults 2) to develop skills in advanced methods for the application to proteomic data, and 3) to develop skills in grant writing, lab management and career development. Dr. Miller will accomplish these objectives through mentorship, coursework, and workshops. She has assembled a multidisciplinary mentorship team comprised of her primary mentor, Dr. Ix, an established leader in nephrology, and the following co-mentors: Dr. Marquine, an expert in neuropsychology; Dr. Scherzer, the Director of Biostatistics at the Kidney Health Research Collaboration at the University of California, San Francisco. Research: CI is a clinical symptom of ADRD, with mild CI being often a precursor to the development of ADRD. CI is common among patients with CKD; however, CI has received much less investigation than complications such as CVD and end-stage kidney disease. Studies have primarily used estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) to evaluate the relationship between CKD and CI. However, in recent work the applicant demonstrated that a panel of markers reflecting kidney tubule health was associated with CI independent of eGFR and ACR in older adults, indicating that these markers of kidney health do not fully explain its link with CI. Still, the relationship is likely more complex that what can be identified using a few targeted biomarkers. Thus, Dr. Miller proposes to utilize large-scale proteomic data to understand the multifactorial relationship between CKD and cognition with the long-term objective that these insights might lead to novel approaches and therapies to prevent or ameliorate the development of CI in the CKD population. Next, while large-scale proteomics is optimally suited to understand biological pathways between CKD and CI, it will not be feasible to utilize in clinical practice to identify individuals at highest risk for CI. As such, variable selection methods are needed to identify and validate subsets of proteins that will allow clinical prediction of cognitive impairment. In aim 1, she will identify protein clusters and biological pathways that associate with CI. This aim will be conducted in 3419 adults with CKD in the Chronic Renal Insufficiency Cohort Study (CRIC). In aim 2 she will test different penalized variable selection methods to identify a panel of proteins that predict CI in the same CRIC cohort. In aim 3, Dr. Miller will determine if the clusters and proteins identified in CRIC externally validate among 1076 older adults with CKD in the Cardiovascular Health Study.

项目摘要 这是Joachim IX的指导 医学博士，圣地亚哥分校（UCSD）。该建议将确定米勒博士为 独立研究者，并将利用大规模蛋白质组学来了解关联和预测 蛋白质组具有认知障碍（CI）的能力，阿尔茨海默氏病及相关的临床症状 慢性肾脏疾病（CKD）老年人的痴呆症（ADRD）。 候选人：米勒博士通过此提案的培训目标和职业目标包括：1）成为一个 CKD和CI的专家在老年人中2）开发高级方法的技能以应用于蛋白质组学 数据和3）发展赠款写作，实验室管理和职业发展方面的技能。米勒·威尔博士 通过指导，课程和研讨会来实现这些目标。她集会了 多学科心态团队完成了她的主要心态，肾脏学领导者IX博士， 以及以下院长：神经心理学专家Marquine博士； Scherzer博士，主任 加利福尼亚大学旧金山分校的肾脏健康研究合作的生物统计学。 研究：CI是ADRD的临床症状，温和的CI通常是发展的前身 adrd。 CI在CKD患者中很常见；但是，CI收到的投资远低于 CVD和末期肾脏疾病等并发症。研究主要使用了估计的肾小球 过滤率（EGFR）和尿白蛋白与肌酐比（ACR）评估CKD与CKD之间的关系 CI。但是，在最近的工作中，适当的作品表明，一组标记反映了肾小管健康 与CI独立于EGFR和ACR相关的老年人，表明这些肾脏标记 健康不能完全解释其与CI的联系。尽管如此，这种关系可能更复杂 使用一些靶向生物标志物确定。米勒博士的提议将大规模蛋白质组学数据用于 了解CKD与认知之间的多因素关系，并以长期目标为 见解可能会导致新的方法和疗法，以预防或改善CI的发展 CKD人口。接下来，大规模蛋白质组学非常适合了解生物途径 在CKD和CI之间，在临床实践中使用最高风险的个体是不可行的 CI。因此，需要使用可变选择方法来识别和验证蛋白质的子集，以允许 认知障碍的临床预测。在AIM 1中，她将识别蛋白质簇和生物学途径 与CI相关。这个目标将在3419名患有CKD的成年人中进行慢性肾功能不全 队列研究（CRIC）。在AIM 2中，她将测试不同的惩罚变量选择方法，以识别一个面板 在同一CRIC队列中预测CI的蛋白质。在AIM 3中，米勒博士将确定簇和蛋白质是否 在心血管健康研究中，在1076名患有CKD的老年人中，在CRIC外部验证中鉴定出来。