個(gè)體化醫(yī)療的現(xiàn)狀與未來(lái)生物標(biāo)志物（PPT）

1、 個(gè)體化醫(yī)療的現(xiàn)狀與未來(lái)個(gè)體化醫(yī)療的現(xiàn)狀與未來(lái) 四四. 生物標(biāo)志物研究生物標(biāo)志物研究 呂林莉 m.d., ph.d. 東南大學(xué)醫(yī)學(xué)院 outline 生物標(biāo)志物的概念 如何評(píng)價(jià)生物標(biāo)志物？ 生物標(biāo)志物的研究方法？ 生物標(biāo)志物的概念生物標(biāo)志物的概念 什么是生物標(biāo)志物什么是生物標(biāo)志物(biomarker)？ “measurable and quantifiable biological parameters” - a medical subject heading (mesh) term, 1989 “ a characteristic that is objectively measured a

2、nd evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.” -biomarker definitions working group, 2001,nih features of a useful biomarker nhigh sensitivity and specificity neasy accessible sample ncorrelation with his

3、tological scoring nchange in advance of clinical signs ntranslational from research to clinical use 不同水平生物標(biāo)志物不同水平生物標(biāo)志物 dna primary transcript mrna transcription protein translationrna processing nucleus biomarker examples cholesterol is one of the most well-known biomarkers of cardiovascular health

4、physical measurements: body temperature (fever); blood pressure (stroke risk) other biomarkers: blood sugar level (diabetes) antigens (hepatitis) proteins (heart attack) genetic variations (huntingtons disease) 生物標(biāo)志物的臨床應(yīng)用生物標(biāo)志物的臨床應(yīng)用 ludwig ja et al. nature reviews 2005,5: 845-856 目前臨床很多疾病的診斷依賴病理診斷， 但

5、不能作為常規(guī)篩查、監(jiān)測(cè)手段 眾多疾病缺乏早期、特異性生物標(biāo)志物 治療缺乏個(gè)體化方案 生物標(biāo)志物應(yīng)用現(xiàn)狀生物標(biāo)志物應(yīng)用現(xiàn)狀 clin j am soc nephrol 3: 18951901, 2008. biomarkers for chronic kidney disease are we treating sub-populations? 疾病疾病藥物藥物無(wú)反應(yīng)率無(wú)反應(yīng)率 抑郁ssris, snris, tcas40-60% 哮喘-adrenergics, ltd44-75% 糖尿病sulfonylurea, biguanides, glitazones 50-75% 腫瘤 (乳腺癌 肺

6、癌) various70-100% from kalow, tyndale 113:2335-2362. the agendia mammaprint test 首個(gè)fda批準(zhǔn)的基因組檢測(cè)試驗(yàn) - feb. 2007 how they got there？ 2002 discovery of 70 gene signature (117 patients) 2002 duplication of results (in another sample set:295 patients) 2006 assay performance 2006 optimized array format: rep

7、roducibility; back to original sample set 2006 external confirmation (307 patients, 5 hospitals) 2007 approval by fda 生物標(biāo)志物研究技術(shù) 傳統(tǒng)研究方法：傳統(tǒng)研究方法： pcr, western blotting, elisa, et al 新型研究方法：新型研究方法： 基因組學(xué)技術(shù) 蛋白質(zhì)組學(xué)技術(shù)：2-dige/ms, 蛋白質(zhì)芯片 生物標(biāo)志物研究方法生物標(biāo)志物研究方法 question1. what human samples should be collected, and

8、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 fluids serum, plasma, urine, csf secretions saliva, seminal flu

9、id 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 study plasma for discovery, and then validate or implement assay

10、 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” fluids like csf, synovial fluid, ascites, pancreatic ductal fluid,

11、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 prognosis monitoring of response to therapy “proximal fluids” can

12、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. must human sample collection be prospective, or can existing r

13、epositories 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 retrospective studies using well characterized samples in repositories can be performed and frequently yield viable candidates 生物標(biāo)志物研究面臨的