Identification of a Multi-Analyte Profile for Primary Hyperoxaluria

原发性高草酸尿症多分析物谱的鉴定

• 批准号: 8011032
• 负责人: James P Mapes
• 金额: $ 41.92万
• 依托单位: RULES-BASED MEDICINE, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-31 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011032
• 关键词: Adolescent; Age; Algorithms; Archives; Automation; Biological Markers; Calcium Oxalate; Calculi; Chicago; Child; Childhood; Citrates; Clinical; Clinical Management; Collaborations; Data; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Effectiveness; End stage renal failure; Ensure; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Future; Gender; Genes; Genotype; Health; Hereditary Disease; Hospitals; Hour; Immunoassay; Individual; Intervention; Kidney; Kidney Calculi; Laboratories; Life; Liver; Measures; Medicine; Modeling; Mutation; Organ; Oxalates; Patients; Pattern; Phase; Phenotype; Physiological; Population; Population Control; Predictive Value; Primary Hyperoxaluria; Proteins; Proteomics; Rare Diseases; Registries; Relative Risks; Renal function; Resource Development; Risk; Sampling; Scientist; Screening procedure; Selection for Treatments; Sensitivity and Specificity; Siblings; Specimen; Supportive care; Technology; Therapeutic; Time; Treatment Effectiveness; Universities; Urine; Validation; Variant; age effect; base; clinical Diagnosis; cohort; cost; dosage; high risk; hypercalciuria; improved; insight; medical schools; meetings; molecular marker; new technology; novel; outcome forecast; pediatric department; prospective; protein expression; protein profiling; response; time use; validation studies

DESCRIPTION (provided by applicant): Primary hyperoxaluria, type 1 (PH1) is a rare, monogenic disorder in which a mutation in the AGXT gene leads to overproduction of oxalate by the liver, resulting in widespread deposition of calcium oxalate in the kidneys and other organs. Unfortunately, PH1 disease progression is not understood. Despite identification of the AGTX mutation, there is little genotype-phenotype correlation in these patients, with kidney stone formation and loss of kidney function proceeding in a seemingly haphazard fashion. Many patients may progress to end- stage kidney disease (ESKD), despite current supportive therapy. An objective diagnostic that accurately detects PH1 and identifies individuals at high risk for rapid progression to ESKD is an unmet clinical need. Clearly, no single molecular marker, or small group of markers, will be able to meet this need. Common proteomic technologies, such as Enzyme-Linked Immunosorbent Assay (ELISA), lack the ability to quantify multiple biomarkers simultaneously. One-at-a-time assessment of each putative biomarker incurs considerable time, cost and sample volume. Newer technologies lack sensitivity, precision and automation. The ability to systematically identify protein profiles, predict risk of clinical events, evaluate therapeutic response, and define underlying mechanisms is thereby limited severely. Rules-Based Medicine (RBM) resolved these limitations by developing bead-based, multiplexed immunoassays for identifying disease-specific Multi-Analyte Profiles (MAPs). Exciting preliminary data indicates that MAP technology is well suited for screening large numbers of markers in parallel to identify protein profiles associated with PH1, and may provide insight into the disease course. During Phase I, RBM, and Children's Memorial Hospital (CMH) propose to utilize this quantitative proteomics approach to compare the protein profiles in urine samples obtained from patients diagnosed with PH1 vs. age- and gender-matched control populations. The level and pattern of expression for 201 proteins will be studied. It is expected that the physiological insight obtained from the proposed study may be used to better define the pathological mechanisms associated with PH1. During Phase II, a prospective validation of the MAP identified for PH1 during Phase I efforts will be performed. The sensitivity, specificity,and positive and negative predictive values for each analyte, as well as, the MAP of biomarkers for predicting progression of the disease to ESKD will be determined. In addition, a proposed physiological range of MAP analytes for children and adolescents will be developed based on age, and gender for both the normal and PH1 populations. Such range values, typically used for diagnosis and intervention, can be used as a reference for future studies and for the development of both a diagnostic test and therapeutic algorithms. The identification of novel biomarker patterns of individuals with PH1, as well as, individuals at high risk for rapid progression to ESKD, will allow for improved management of the condition by objective selection of treatment course or dosage, determining treatment effectiveness, and providing a framework for developing and evaluating new treatments. PUBLIC HEALTH RELEVANCE: Primary hyperoxaluria, type 1 (PH1) is a rare, genetic disorder that leads to widespread deposition of calcium oxalate stones in the kidneys and other organs. Unfortunately, PH1 disease progression is not understood, and many patients may progress to end-stage kidney disease, despite therapy. The identification of novel biomarker patterns of individuals with PH1 as well as, individuals at high risk for progression to end-stage kidney disease, will allow for improved management of the condition by objective selection of treatment course, aiding the determination of treatment dosage and/or effectiveness, and providing a framework for developing and evaluating new treatments.

描述（由申请人提供）：原发性高尿酸血症1型（PH 1）是一种罕见的单基因疾病，其中AGXT基因突变导致肝脏草酸盐过量产生，导致草酸钙在肾脏和其他器官中广泛沉积。不幸的是，PH 1疾病进展尚不清楚。尽管发现了AGTX突变，但这些患者的基因型与表型几乎没有相关性，肾结石形成和肾功能丧失似乎是以随意的方式进行的。尽管目前有支持性治疗，许多患者仍可能进展为终末期肾病（ESKD）。准确检测PH 1并识别快速进展为ESKD的高风险个体的客观诊断是一个未满足的临床需求。显然，没有一个单一的分子标记或一小群标记能够满足这一需求。常见的蛋白质组学技术，如酶联免疫吸附测定（ELISA），缺乏同时定量多种生物标志物的能力。对每种假定的生物标志物进行一次一次的评估会花费大量的时间、成本和样本量。较新的技术缺乏灵敏度、精确度和自动化。因此，系统鉴定蛋白质谱、预测临床事件风险、评价治疗反应和确定潜在机制的能力受到严重限制。基于规则的医学（RBM）通过开发基于珠的多重免疫测定来识别疾病特异性多分析物谱（MAP），从而解决了这些限制。令人兴奋的初步数据表明，MAP技术非常适合平行筛选大量标记物，以识别与PH 1相关的蛋白质谱，并可提供对疾病过程的深入了解。在第一阶段，RBM和儿童纪念医院（CMH）建议利用这种定量蛋白质组学方法来比较从诊断为PH 1的患者与年龄和性别匹配的对照人群中获得的尿样中的蛋白质谱。将研究201种蛋白质的表达水平和模式。预计从拟议的研究中获得的生理学见解可用于更好地定义与PH 1相关的病理机制。在第II阶段，将对在第I阶段工作期间为PH 1确定的MAP进行前瞻性验证。将确定每种分析物的灵敏度、特异性、阳性和阴性预测值，以及用于预测疾病进展为ESKD的生物标志物的MAP。此外，将根据正常人群和PH 1人群的年龄和性别，制定儿童和青少年MAP分析物的拟定生理范围。通常用于诊断和干预的这种范围值可以用作未来研究以及诊断测试和治疗算法的开发的参考。鉴定PH 1个体以及快速进展为ESKD的高风险个体的新型生物标志物模式，将允许通过客观选择治疗过程或剂量，确定治疗有效性并提供开发和评估新治疗的框架来改善病情的管理。公共卫生关系：原发性高尿酸血症1型（PH 1）是一种罕见的遗传性疾病，可导致草酸钙结石在肾脏和其他器官中广泛沉积。不幸的是，PH 1疾病进展尚不清楚，许多患者尽管接受治疗，仍可能进展为终末期肾病。鉴定PH 1个体以及进展为终末期肾病的高风险个体的新生物标志物模式，将允许通过客观选择治疗过程来改善病情的管理，帮助确定治疗剂量和/或有效性，并为开发和评估新治疗提供框架。