Multi-Omics and Chronic Kidney Disease: Correlation with Histology

多组学和慢性肾脏病：与组织学的相关性

• 批准号: 10663386
• 负责人: Morgan Erika Grams
• 金额: $ 71.3万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663386
• 关键词: Acetylation; Acetyltransferase; Address; African American; African American population; Albuminuria; American; Amino Acids; Applied Genetics; Atherosclerosis Risk in Communities; Atrophic; Biological; Biological Assay; Biological Markers; Biological Process; Biopsy; Blood; Blood Proteins; Boston; Caring; Cells; Chronic Kidney Failure; Clinical; Clinical Pathways; Cohort Studies; Collaborations; Computerized Medical Record; Data; Development; Diagnosis; Dialysis procedure; Disease; Disease Marker; Disease Progression; Early Diagnosis; End stage renal failure; Etiology; Exhibits; Fibrosis; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Techniques; Glomerular Filtration Rate; Goals; Grant; Hand; Heterogeneity; Histologic; Histology; Histopathology; Hypertension; Individual; Inflammation; Investigation; Kidney; Kidney Diseases; Knowledge; Link; Measures; Mendelian randomization; Metabolic; Methods; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Phase; Plasma; Population Heterogeneity; Procedures; Process; Productivity; Prognosis; Protein Biosynthesis; Proteins; Proteomics; Publications; Publishing; Quantitative Trait Loci; Renal Replacement Therapy; Renal function; Request for Proposals; Research; Research Personnel; Resolution; Risk; Role; Sclerosis; Severity of illness; Technology; Time; Tissues; Transplantation; Tubular formation; Variant; Visit; Work; adjudication; adverse outcome; biobank; biomarker identification; cell type; clinically relevant; cohort; genome wide association study; genomic data; glomerular filtration; glomerulosclerosis; high risk; improved; innovation; insight; interest; interstitial; kidney biopsy; link protein; metabolomics; multiple omics; novel; podocyte; precision medicine; protein biomarkers; statistics; therapeutic candidate; therapeutic target

ABSTRACT Half of all Americans will develop chronic kidney disease (CKD) during their lifetime. Risk for progressive CKD is particularly high among African Americans: an estimated 7-8% will eventually require kidney replacement therapy, such as dialysis or transplant. Existing treatment for CKD is inadequate, and far greater mechanistic insight is required to explain and address heterogeneity in disease progression. The proposed study will use a combination of innovative methods and omics data to identify biomarkers and pathways that are clinically relevant, linking blood protein and metabolite levels to kidney outcomes and kidney histology. The first phase of this grant focused on integrating genetic and metabolomic data in two cohorts of African Americans, the African American Study of Kidney Disease and Hypertension (AASK) and a subset of BioME, an electronic medical record-linked biorepository. The initial grant period was highly productive, with more than 22 publications, and a focus on rigorous replication of findings in multiple research and clinical cohorts. The renewal proposal requests funds for integrating novel proteomic data with existing metabolomic and genomic data in AASK (proteomic profiling of 7,000 proteins at the baseline visit funded in year 5 of the initial grant period) and expansion to the Boston Kidney Biopsy Cohort Study (BKBC), a clinical cohort with adjudicated histological scores of CKD pathology. Our overarching hypothesis is that an integrated approach combining genetics, proteomics, metabolomics, and histological correlates can yield novel insights into the pathogenesis and prognosis of CKD. Additional investigation using data from genetics consortia and the Kidney Precision Medicine Project will permit corroboration of potential causal roles in disease development and compartment- specific expression of select markers highlighted by our BKBC analyses at single cell resolution, respectively. If successful, these studies should (a) identify key metabolites, proteins, and networks that provide information about risk of CKD progression independent of GFR, albuminuria, and other confounders; (b) identify blood metabolite and protein markers of specific renal histopathologic findings, including interstitial fibrosis/tubular atrophy (IFTA), glomerular sclerosis, and arterial/arteriolar sclerosis; and (c) determine the potential causal role of metabolite and protein markers in CKD pathogenesis. The data generated from this grant would be largely unprecedented in scope, connecting histology and omics, and work in AASK greatly increases the diversity of populations represented in omic investigations. Methods developed will have broad applicability, and the investigators are well poised to extend and replicate findings in other cohorts. Finally, this proposal will be executed by a team with a track record of collaboration and published expertise in each of the methods outlined in the application, demonstrating a high level of feasibility.

摘要

项目成果

APOL1 Risk Alleles, Cardiac Markers, and Risk of ESKD in African Americans: The Atherosclerosis Risk in Communities Study.

非裔美国人中的 APOL1 风险等位基因、心脏标志物和 ESKD 风险：社区研究中的动脉粥样硬化风险。

• DOI: 10.1016/j.xkme.2020.02.007
• 发表时间: 2020
• 期刊: Kidney medicine
• 影响因子: 3.9
• 作者: Surapaneni,AdityaL;Ballew,ShoshanaH;Coresh,Josef;Ballantyne,ChristieM;Selvin,Elizabeth;Matsushita,Kunihiro;Grams,MorganE
• 通讯作者: Grams,MorganE

Epidemiology research to foster improvement in chronic kidney disease care.

• DOI: 10.1016/j.kint.2019.11.010
• 发表时间: 2019-11
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Shengyuan Luo;M. Grams

Serum 6-Bromotryptophan Levels Identified as a Risk Factor for CKD Progression.

血清 6-溴色氨酸水平被确定为 CKD 进展的危险因素。

• DOI: 10.1681/asn.2017101064
• 发表时间: 2018
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Tin,Adrienne;Nadkarni,Girish;Evans,AnneM;Winkler,CherylA;Bottinger,Erwin;Rebholz,CaseyM;Sarnak,MarkJ;Inker,LesleyA;Levey,AndrewS;Lipkowitz,MichaelS;Appel,LawrenceJ;Arking,DanE;Coresh,Josef;Grams,MorganE
• 通讯作者: Grams,MorganE

Serum metabolites are associated with all-cause mortality in chronic kidney disease.

• DOI: 10.1016/j.kint.2018.03.008
• 发表时间: 2018-08
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Hu JR;Coresh J;Inker LA;Levey AS;Zheng Z;Rebholz CM;Tin A;Appel LJ;Chen J;Sarnak MJ;Grams ME
• 通讯作者: Grams ME

Sickle cell trait, estimated glomerular filtration rate, and risk of adverse outcomes in chronic kidney disease.

镰状细胞性状、估计肾小球滤过率以及慢性肾脏病不良后果的风险。

• DOI: 10.1002/ajh.25588
• 发表时间: 2019
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Sood,Rupali;Surapaneni,Aditya;Luo,Shengyuan;Appel,LawrenceJ;Winkler,Cheryl;Grams,MorganE;Naik,RakhiP
• 通讯作者: Naik,RakhiP