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.

项目概要 这是 Lindsay Miller 博士在 Joachim Ix 的指导下首次提交的 K01 申请 加州大学圣地亚哥分校 (UCSD) 医学博士 该提案将确立米勒博士为一名医学博士。 独立研究者，将利用大规模蛋白质组学来了解关联性和预测性 蛋白质组与认知障碍（CI）的能力，认知障碍是阿尔茨海默病及相关的临床症状 患有慢性肾病 (CKD) 的老年人出现痴呆 (ADRD)。 候选人：米勒博士通过本提案的培训目标和职业目标包括： 1) 成为一名 老年人 CKD 和 CI 专家 2) 培养应用于蛋白质组学的先进方法技能 数据，3) 培养米勒博士的资助写作、实验室管理和职业发展技能。 她通过指导、课程作业和研讨会来实现这些目标。 多学科指导团队由她的主要导师 Ix 博士组成，Ix 博士是肾脏病学领域的知名领导者， 以及以下共同导师： Marquine 博士，神经心理学专家；Scherzer 博士，该中心主任； 旧金山加利福尼亚大学肾脏健康研究合作组织的生物统计学。 研究：CI 是 ADRD 的一种临床症状，轻度 CI 通常是 ADRD 发展的先兆 ADRD 在 CKD 患者中很常见，但对 CI 的研究要少得多。 CVD 和终末期肾病等并发症的研究主要使用估计的肾小球。 滤过率（eGFR）和尿白蛋白肌酐比（ACR）来评估 CKD 与 然而，在最近的工作中，申请人证明了一组反映肾小管健康的标记物。 与老年人的 CI 相关，与 eGFR 和 ACR 无关，表明这些肾脏标志物 健康并没有完全解释其与 CI 的联系，但这种关系可能比实际情况更为复杂。 因此，米勒博士建议利用大规模蛋白质组数据来识别。 了解 CKD 与认知之间的多因素关系，长期目标是这些 见解可能会带来新的方法和疗法来预防或改善 CI 的发展 其次，大规模蛋白质组学最适合了解生物途径。 在 CKD 和 CI 之间，在临床实践中利用来识别具有最高风险的个体是不可行的 因此，需要变量选择方法来识别和验证允许的蛋白质子集。 在目标 1 中，她将识别蛋白质簇和生物途径。 该目标将在 3419 名患有慢性肾功能不全的 CKD 成人中进行。 队列研究 (CRIC) 在目标 2 中，她将测试不同的惩罚变量选择方法来确定一组。 在同一 CRIC 队列中预测 CI 的蛋白质 在目标 3 中，Miller 博士将确定簇和蛋白质是否相同。 CRIC 在心血管健康研究中对 1076 名患有 CKD 的老年人进行了外部验证。