2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/655135摘要：一、研究背景與目的老年性聽損是已開發國家中聽力障礙最常見的原因，隨著人口組成的逐年老化，老年性聽損勢必將成為社會之一大負擔，也將是臨床工作者所必須面對之一大挑戰。過去的遺傳研究及動物研究均清楚指出老年性聽損與基因因素之關連性，同時也發現其遺傳模式顯非由僅單一基因所導致，至於其詳細機轉，則仍未知。而隨著後基因體時代的來臨，吾人寄望相關的基因科技與生物資訊，能使我們對老年性聽損有更進一步的了解，甚至能應用於預防醫學與治療醫學。關於成因可能由多基因與環境因素共同作用而成之「複雜性狀」疾病，基因研究方法之發展係由最傳統之候選基因策略(candidate gene approach)、全基因組關聯分析(genome-wide association study, GWAS)、乃至次世代定序技術(next generation sequencing)，而各種研究方式均有其優缺點。於本研究中，我們將應用候選基因策略及次世代定序技術等研究方法，進行相關的基因研究，希望有助於釐清國人老年性聽損的致病機制。而在候選基因策略及次世代定序技術之研究中，若發現與人類老年性聽損相關的基因變異，我們亦將進一步培育其相對應的基因轉殖鼠，以建立老年性聽損的實驗動物模式。二、研究方法本計畫之設計為前瞻性基因研究，共分為三大部分：1. 應用候選基因策略，釐清Klotho基因、FGF23基因與老年性聽損之關聯：將自吾人老年性聽損世代3000名受試者中，區別實驗組與對照組以進行之。2. 應用次世代定序技術，研究可能導致老年性聽損之罕見基因變異：於3000名受試者，挑選具極端表現型者(即聽力最佳、最差)各1%計60人後，應用次世代定序技術掃描此60人在70個聽損相關基因是否具導致老年性聽損之罕見變異。3. 實驗動物模式之建立：基於前二部分之研究成果，進一步培育其相對應的「基因置換鼠」(knock-in mouse)，以建立老年性聽損的實驗動物模式。三、預期成果1. 建立一大規模之國人老年性聽損樣本庫，並釐清其流行病學資料。2. 釐清Klotho基因、FGF23基因與老年性聽損之關聯，並評估其作為一臨床上預後指標之可能性。3. 應用次世代定序技術，發現可能導致老年性聽損之罕見基因變異。4. 老年性聽損實驗動物模式之建立，日後可應用於轉譯研究或臨床研究，如預防或治療老年性聽損新藥物的研發等。5. 本計畫之研究成果，將有助於臨床醫師或聽力師正確評估病人發生老年性聽損的原因，乃至於作為處理、治療時之參考。6. 所有研究人員可以從中獲得有關基因關聯研究之設計與統計、次世代定序技術之操作與分析、基因轉殖鼠之培育等相關技術及方法。<br> Abstract: Background and Objectives:Age-related hearing impairment (ARHI), or presbycusis, is a major public health problem. About 40% of people older than 65 years have a hearing loss severe enough to impair communication. The number of people suffering from ARHI is anticipated to increase significantly with the rapid aging of population. Both genetic and environmental factors contribute to the development of ARHI. Possible environmental risk factors for ARHI include occupational or recreational noise exposure, exposure to ototoxic medication, hypertension, cardiovascular disease, renal disease and smoking. In contrast, less is known about the genetic involvement in ARHI, although the heritability of ARHI has been well documented in previous studies.Several approaches have been developed to investigate the genetic component of complex polygenic and multifactorial diseases, such as ARHI. The purpose of the present study is to explore the genetics of ARHI using the candidate gene approach and the next generation sequencing (NGS) technique, respectively. If ARHI-related genetic variants are identified, animal models will also be established accordingly for functional genetic studies.Materials and Methods:The present project comprises the following 3 parts:1. Investigating the association between ARHI and the Klotho and FGF23 genes using the candidate gene approach in an ARHI cohort composed of 3000 subjects.2. Identifying rare variants that might contribute to ARHI using NGS. Sixty subjects with the 1% extreme phenotype (i.e. the 1% best/worst hearing) will be selected from the ARHI cohort, and subjected to NGS of 70 deafness-associated genes.3. Based on the results of the prior 2 parts of studies, knock-mice with specific genetic variants will be created to establish animal models for ARHI.Anticipated Results:The results of the project will shed light on the genetics of ARHI. The association between ARHI and the Klotho and FGF23 genes will be clarified. Rare genetic variants contributing to ARHI may be identified. The information will help clinicians address their patients with ARHI. The establishment of animal models for ARHI will also facilitate translational studies and pharmacogenetic studies in the future.老年性聽損候選基因策略Klotho基因FGF23基因次世代定序基因置換鼠Age-related hearing impairmentcandidate gene approachKlotho geneFGF23 genenext generation sequencingknock-in mouse