2018-04-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658852摘要：巴金森氏症 (PD) 是目前最常見的神經退化疾病之一，據預測患者將由 2005年統計的460萬人，於2030年增加兩倍，達870-930萬人，根據統計，台灣目前約有超過4.2萬名患者。神經內 alpha-synuclein 逐漸累積於 Lewy bodies 及 dopaminergic neuron 逐步退化是PD的重要病理指標。目前PD的治療仍限於支持療法，病患症狀仍會隨年齡老化而惡化。因此，我們迫切需要了解更精確的PD致病分子及細胞機轉，發展機理性療法，以有效抑制神經退化症狀。本計畫將結合基礎及臨床研究團隊，連結系統生物學中心及國際知名、對台灣PD患者的基因變異與對巴金森致病基因,LRRK2,有長期深入研究的臺大醫院巴金森氏症暨動作障礙中心。PD的病因乃因老化與基因及環境危險因子交互作用所致，為探討詳細之分子致病機轉，以期發展未來以機轉為導向的根本治療，我們連結分子及細胞生物學、遺傳及基因體學及基礎與臨床神經科學的傑出學者，共同研究此挑戰性課題。本計畫包含九項研究計畫，並結合系統生物學核心平台，以互相支援及強化此整合型計畫。以細胞及個體的尺度，研究與LRRK2突變相關，並影響alpha-synuclein 動態/聚集之細胞內、外及環境等因子。同時，比較PD起始到致病間，腦-腸道-微生物相與內分泌免疫及神經迴路間複雜的交互作用。亦將找出造成不同年齡發病及不同發病階段之患者的可能致病分子及其致病特色，預期實驗成果不僅可以釐清巴金森症神經系統退化之機制，並將發展機理性之PD療法。並由系統生物學中心的體學、次世代定序及生物資訊分析核心平台的支援，整合各項實驗數據，對交互反應之網絡進行多因子分析，以解析PD的致病模式。本計畫亦將與基因體與系統生物學學程合作，積極訓育系統生物學及神經退化相關領域研究人才。我們邀請對深入研究多因子致病疾病的美國 UC Irvine複雜生物學系統中心主任 Dr. Arthur Lander 為本中心的諮詢專家協助，期望建立傑出PD基礎與臨床研究殿堂，同時促進相關教育，並於未來提供預防及治療的有效策略，以促進社群健康。<br> Abstract: Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. It was estimated that the number of people with PD will rise from 4.1 to 4.6 million in 2005 by two times to 8.7 to 9.3 million in 2030. Aggregation of intra-neuronal alpha-synuclein into Lewy bodies and progressive dopaminergic neuron degeneration are pathological hallmarks of this disease. Currently, PD treatments are mainly limited to supplement therapy, and PD symptoms still progressively deteriorate with age. It is urgent to understand the precise molecular and cellular mechanisms of PD pathogenesis and develop mechanism-targeted strategies to halt or ameliorate neurodegeneration. We have formed a strong basic and clinical research team, aiming to provide solutions to these unmet needs through a joint effort of Center for Systems Biology (CSB) and Centre for Parkinson and Movement Disorders (CPMD) at National Taiwan University Hospital. CPMD, one of the world leading PD centers, has experience and reputation in studies of the PD risk factor LRRK2, especially LRRK2 variants with Taiwanese-enriched mutations. As PD is recognized as a multifactorial disease, with variable contributions of genetic susceptibility and environmental factors, we have recruited distinguished experts in molecular and cell biology, genetics and genomics, and basic and clinical neuroscience to address the challenging issues. We propose nine interconnected research subprojects and a systems biology platform that supports and empowers research subprojects in this Joint Project. Specifically, we plan to investigate intracellular, extracellular and environmental factors that alter intracellular alpha-synuclein dynamics/aggregation at the cellular and organismal levels, in conjunction with LRRK2 mutations. In addition, we plan to dissect the complex molecular interactions in the brain-gut-microbiota axis with endocrine-immune pathways and neural circuits, in initiation and manifestation of PD. Moreover, we will identify and characterize molecules featuring different onset ages and pathological stages of PD patients. Finally, we will develop mechanism-based therapeutic strategies based on our basic and clinical research. Using the systems biology platform in CSB, including proteomics/metabolomics, next generation sequencing and bioinformatics, we could combine all results together as an interaction network for multi-factor analysis of disease mechanism with bioinformatic pipeline tools. Furthermore, we will work closely with the joint NTU-Academia Sinica Graduate Program in Genome and Systems Biology (GSB) to provide students rigorous training in system biology and neurodegeneration-related fields. We have invited Dr. Arthur Lander, Director of the Center for Complex Biological Systems at University of California, Irvine, and an expert in multi-factorial disease, as a consultant in CSB. Our vision is to establish a reputable research precinct with strong basic and clinical research on PD, while facilitating education, providing prevention and treatment strategies of PD for a healthy society in the future.巴金森氏症神經退化alpha-synucleinLRRK2腦-腸軸微生物相自噬作用溶小體外泌體系統生物學Parkinson’s diseaseneurodegenerationalpha-synucleinLRRK2brain-gut axismicrobiotaautophagylysosomeexosomesystems biology