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1、个体化医疗的现状与未来四. 生物标志物研究,吕林莉 M.D., Ph.D. 东南大学医学院,Outline,生物标志物的概念 如何评价生物标志物？ 生物标志物的研究方法？,生物标志物的概念,什么是生物标志物(biomarker)？,“measurable and quantifiable biological parameters” - a Medical Subject Heading (MeSH) term, 1989 “ A characteristic that is objectively measured and evaluated as an indicator of norma
2、l biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.” -Biomarker Definitions Working Group, 2001,NIH,Features of a Useful Biomarker,High sensitivity and specificity Easy accessible sample Correlation with histological scoring Change in advance of c
3、linical signs Translational from research to clinical use,不同水平生物标志物,DNA,Primary transcript,mRNA,Transcription,protein,Translation,RNA processing,Nucleus,Biomarker Examples,Cholesterol is one of the most well-known biomarkers of cardiovascular health Physical measurements: body temperature (fever); b
4、lood pressure (stroke risk) Other biomarkers: blood sugar level (diabetes) antigens (hepatitis) proteins (heart attack) genetic variations (Huntingtons disease),生物标志物的临床应用,Ludwig JA et al. Nature reviews 2005,5: 845-856,目前临床很多疾病的诊断依赖病理诊断，但不能作为常规筛查、监测手段 众多疾病缺乏早期、特异性生物标志物 治疗缺乏个体化方案,生物标志物应用现状,Clin J Am
5、 Soc Nephrol 3: 18951901, 2008.,Biomarkers for chronic kidney disease,Are we treating sub-populations?,From Kalow, Tyndale 113:2335-2362.,The Agendia MammaPrint Test 首个FDA批准的基因组检测试验 - Feb. 2007,How they got there？,2002 Discovery of 70 gene signature (117 patients) 2002 Duplication of results (in ano
6、ther sample set:295 patients) 2006 Assay performance 2006 Optimized array format: reproducibility; back to original sample set 2006 External confirmation (307 patients, 5 hospitals) 2007 Approval by FDA,生物标志物研究技术,传统研究方法： PCR, Western blotting, ELISA, et al 新型研究方法： 基因组学技术 蛋白质组学技术：2-DIGE/MS, 蛋白质芯片,生物标
7、志物研究方法,Question1. What human samples should be collected, and how should they be used? Does this vary between discovery, validation and implementation?,Answer1.,All biological samples are eligible for collection Collected biological material depends on analyte and tissue source Examples Biological f
8、luids Serum, plasma, urine, csf Secretions Saliva, seminal fluid Body cavity fluids Pleural fluid, peritoneal fluid, etc Specific tissue material Specialized cells reproductive cells Non-cellular,Ideal Biomarker discovery samples should be identical to the projected testing situation (e.g. Do not st
9、udy plasma for discovery, and then validate or implement assay using serum) Practical set up study with samples that are as close to the testing situation as possible,Question 2.,What is the role of routinely accessible biofluids such as plasma, serum, and urine? What is the role of “proximal” fluid
10、s like CSF, synovial fluid, ascites, pancreatic ductal fluid, etc? What is the role of solid tissues?,Role of routinely accessible biofluids,Very important in the discovery of biomarkers of diseases (systemic vs. organ specific/local) Important for: early detection disease severity tumor burden prog
11、nosis monitoring of response to therapy,“Proximal fluids” Can reflect disease perturbations in the organs or tissues from which they are secreted Solid tissues Very important for the development of novel insitu biomarkers Immunofluorescence, immunocytochemistry Imaging mass spectrometry,Question 3.,
12、Must human sample collection be prospective, or can existing repositories be used? What considerations are important in determining the adequacy of repository samples?,Answer3:,Ultimate confirmation of the validity of a biomarker has to be proven in a prospective study Nevertheless, well designed re
13、trospective studies using well characterized samples in repositories can be performed and frequently yield viable candidates,生物标志物研究面临的挑战,The multidisciplinary nature of biomarker discovery & development Complex Multiple disciplines Heterogeneous populations Standards not established Expensive Human resources Multiple technologies,