Neurodegenerative Diseases Research Team
PI: Jin-Chung Chen, Ph. D
Research Expertise: Parkinson's Disease, Depression, Drug Addiction
Dr. Jin-Chung Chen, Ph.D.; Dr. Chin-Song Lu, M.D.; Dr. Hung-Li Wang, Ph.D., Dr. Chun-Mao Yang, Ph.D.; Dr. Ing-Tsung Hsiao, Ph.D.; Dr. Jiun-Jie Wang, Ph.D.; Dr. Chien Chou, Ph.D.; Dr. Rong-Chi Huang, Ph.D.; Dr. Guo-Jen Huang, Ph.D.
The goal of Division of Neurodegenerative Diseases, HARC is to advance our current knowledge and explore novel biomarkers and bio-signature in neurodegenerative diseases, in particular two major ageing diseases in the central nervous system, i.e. Parkinson’s disease (PD) and Alzheimer’s disease (AD). The AD and PD represents the leading two neurodegenerative diseases world-wide. Based on the statistics, more than 200 billion medical-related capital costs were spent on AD/PD in USA and it is in general believed the figure will be increasing providing lifespan prolongs. In Taiwan, the patients in AD/PD and other neurodegenerative diseases will expect to be doubled in next 20 years, reaching 200-300 thousands. Hence, understanding the etiology of neural degeneration, mechanism of disease progress or identifying early diagnostic biomarker(s) or bio-signature would be essential to combat the AD/PD or other neurodegenerative disease in order to cut-down the social cost and enhance our welfare.
Both PD and AD have familial and idiopathic causes, with the latter outnumbers the former. Since the discovery of the diseases during early twenty century, there are multiple factors known to contribute individually or in combination the progress of PD or AD. The similarity between PD and AD is the feature of abnormal protein aggregation in particular brain region, i.e. b-amyloid deposits and abnormal tau-protein phosphorylation in AD and Lewy body formation of the PD. So far, there are AD1-AD4 genes (amyloid precursor protein [APP], apolipoprotein E4, presinillin 1 and 2) encoded protein targets/risk factor that would contribute to the pathological phenotypes of the AD, eventually display explicit clinic symptoms includes the hallmark amnesia. Except the standard acetylcholinesterase inhibitor (tarcrine and donepezil) or nootropics, pharmacological therapeutics against AD are rather limited. As for PD, once the disease was simply characterized by the loss of neurotransmitter dopamine in the striatum (nucleus caudate and putamen), thus characteristic movement disorder and resting tremor make sense of the designated functions for dopamine and post-synaptic acetylcholine neurons in this brain region. Medication via dopaminergic strategy thus is the pharmacological mainstay against PD, however suffered with profound side effects (dyskinesia and on-off syndrome) after chronic use. With advances in knowledge of PD, there are PARK1-PARK14 genes now are known to contribute the disease progress, ultimately disrupt the striatal dopamine function and cause motion deficit. With the help of molecular tools plus the specific neurotoxin, various genetic engineered mice or toxin-treated animals were validated for animal models in PD/AD. The success of knock-out or transgenic approaches not only facilitates the understanding of disease progress but provides a useful platform for potential drug screening or gene therapy on novel target(s). In addition, the use of advanced technique such as induced pluripotent stem cell (iPS), one could de-differentiate the diseased neuronal cells into progenitor/stem phenotypes for mechanistic study. Group in neurodegenerative diseases, HARC will adopt various aspects of advanced knowledge in PD and AD to form program project, apply cutting edge technology (piggyBac iPS, genomic, next-generation sequencing, proteomic, molecular imaging and metabolomics) for systemic and molecular approaches.
Taking advantage of extensive resources in Chang-Gung clinical sector and creditable research teams in both Chang-Gung University and Memorial Hospital (Physiology and Pharmacology, Neurology, Neurosurgery, Psychiatry and Nuclear Medicine), our ultimate goal is to bridge the novel clinic findings with basic research and verify in unique model systems, i.e. cell line or animal models. For these purposes, we propose several key research topics to be addressed and the establishment of essential research platforms to cope with our research attempts. The basic structure of research platforms for neurodegenerative diseases study will be served for (a) acquisition of massive database obtained from genomic, proteomic and metabolomics approaches, and (b) evaluation the database (either domestic collected or international collaboration) through various in vivo and in vitro models for ultimate systemic integration.
The specific aims of neurodegenerative disease research group in HARC are to provide molecular and cellular mechanism of key regulators that are known to participate the neuropathogenesis of PD, AD and other neurodegenerative diseases. Based on the extensive experience of the PIs in different area of neuroscience, we will apply multiple aspects of research and approach from systemic to cellular. In addition, we will collaborate in an intimate research team to generate a framework analysis in order to achieve high profile research results. In this regards, we will apply various animal and cellular models to pinpoint important questions and provide in-depth mechanisms from molecular, cellular to behavioral level. The proposed research studies fall into some major areas, i.e. PD, AD and neuroinflammation-related diseases/disorders. Our research team will collaborate intimately with clinical team in Chang-Gung Memorial Hospital, in particular Neuroscience Research Center (NRC) for sharing the database and creating unique transgenic, knonck-in, knock-out mice or piggyBac iPS cell line based on human genetic analyses from familial PD patients.
(1) Biomarker and Bio-signature identification: The importance of early diagnostic biomarkers or risk factor identification reflects not only in cost and effectiveness of clinical treatment, but the successiveness of disease curability. In both PD and AD, there are approximately 10-15% of the causes belongs to nonfamilial type in contrast to 85% of idiopathic (or familial type). Both genetic biomarkers and risk factors would determine the progress and fate of neural degeneration. Considering these two factors are partly could be universal, while significant parts are influenced by local environmental factors and family gene traces, it is essential to establish the domestic biobank to strengthen our research competitiveness around the world. Taking advantage of CGMH available biobank that includes the collection from cerebrospinal fluid (CSF), serum, urine or autopsy brain tissues from PD/AD and other neurodegenerative disease patients, in addition to normal age-matched healthy controls, analyzed samples are well-organized and could be easily referenced. The success of biobank establishment in PD/AD research allows detailed human genetic analyses in addition to comparison with valuable brain scans from Molecular Imaging Center (the PET, SPECT, fMRI and CT scan), Genomic Center, Proteomic Center and Metabolomic platform to construct a comprehensive patient database. Other than –omics detection, the sensitive SPR technique developed by Dr. Chien Chou, faculty of Graduate Institute of Electro-optical engineering, would allow a-synuclein and b-amyloid detection in trace amount hence could facilitate the disease early diagnosis.
(2) Cell and animal model establishment: In Parkinsonism study, research team has been successively produced pathogenic PINK1 and LARK2 Tg or KO mice and will continue to (A) investigate different PD candidate genes and explore how these gene products would lead to protein aggregation, behavioral abnormality and dopamine dysfunction; (B) uncover the underlying cellular mechanism of L-dopa-induced dyskinesia (LID) using 6-OHDA neurotoxin treated semi-PD mice as model and (C) examine how b-amyloid would interact with muscarinic receptor and HO-2 signaling to disrupt the circadian rhythm, an early symptom of AD; and (D) inspect how the pro-inflammatory mediators (such as bradykinin, IL-1b) and NADPH oxidase activation would lead to neuron/glia dysfunction and its involvement in metalloprotenase over-expression and MAPK/NF-kB signaling.
(3) Domestic and international collaboration: One important goal served in the Neurodegenerative research team is to advance and expand our current research capability in order to collaborate with domestic and international research teams. Currently, NRC of CGMH has long-term collaboration with Erasmus medical center at Rotterdam, Netherlands for identifying the genetic variants from domestic familial PD patients. In addition, molecular imaging team participates extensively with numerous research centers and clinical sectors for international cohort study. Based on established platforms in HARC and disease animal models in Division of Neurodegenerative diseases, we expect to expand our research capacity in the future, increase international collaborations and become an international recognized AD/PD research center.
Overall, the established human genetic database and brain imaging profile in NRC, CGMH and disease animal and cell models in HARC would serve as valuable platforms that will benefit not only the research advance in neurodegenerative diseases, but could extensively apply to other neurological or psychiatric disorders (such as Schizophrenia and Major depression). The setup of these platforms, along with others in CGU, will be foreseeable to benefit in both research and teaching (both clinic and basic) and intensify the in-depth of our neuroscience study in Chang-Gung medical research.
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