Abstract
摘要:精神分裂症是一種造成沈重社會負擔的重大精神疾患,影響約1%的人口,也是具有強烈遺傳傾向的多因子心智疾患。越來越多證據顯示若干候選基因(包括AKT1與Neuregulin 1)參與了精神分裂症的致病歷程;同時也發現後天環境因子(如藥物濫用及免疫感染)對於精神分裂症的致病性扮演調控的角色。相較於人類遺傳學的研究限制,以基因突變小鼠為模式更能直接探究候選基因在致病性上的因果關係。奠基於我們團隊近年對Akt1的研究成果,我們將進一步利用Akt1與neuregulin 1基因缺損異型合子小鼠為模式,從跨領域的整合取向去研究基因與基因之交互作用對於精神分裂症相關之行為、認知與社會功能、與神經生物的影響,以及基因與環境危險因子之交互作用如何造成精神分裂症相關症狀的產生。五個主要研究目標為:
(1)描繪基因缺損對於小鼠基本行為功能的影響。
(2)評估基因缺損對於小鼠精神分裂症相關之認知、社會、與注意力功能所造成的影響。
(3)檢驗基因缺損對神經生物與神經病理所造成的影響。
(4)研究基因與環境之交互作用在特定發展階段所造成的影響。
(5)在離體與活體上探索及篩選可能的治療藥物及效果。
本研究將有助於瞭解精神分裂症相關之基因-基因及基因-環境交互作用,也有助於相關藥物篩選。
Abstract: Schizophrenia is a costly and devastating mental disorder that afflicts approximately 1 percent of the worldwide population. It appears to be a multifactorial disorder with a strong genetic predisposition. Accumulating evidence from human genetic studies suggests that multiple susceptibility genes might contribute to the pathogenesis of schizophrenia, including AKT1 (protein kinas Bα) and Neuregulin 1 (NRG1). Human genetic studies also suggest that these genetic deficits affect risk for schizophrenia and accompanying attentional and cognitive impairments. Both AKT1 and NRG1 have a wide range of functions in the developing and adult central neruvous system. Recent findings also indicate that AKT is a key signaling intermediate downstream of dopamine D2 receptor, the best-established target of antipsychotic drugs, and NRG-1 acts in a paracrine fashion to stimulate PI3-kinase/AKT signaling pathway which might be related to delusional ideation. While evidence indicates a genetic basis for schizophrenia, the concordance rate in homozygotic twins inflicting schizophrenia never reaches 50%, suggesting epigenetic involvement in this disorder. Drug abuse and early infection induced disruption of neurodevelopment may predispose the organism to long-lasting changes and lead to the onset of schizophrenia in later life. It is conjectured that exposure to psychostimulants or viral infection encountered at certain critical periods for brain development may be a factor of precipitating the schizophrenic symptoms in a genetic prone population. Compared with studies in human patients, genetic mouse models of schizophrenia is a simple and relatively straightforward approach for determining the causal relationships. Using gene knockout or transgenic techniques to develop mice with targeted mutations uniquely enables the identification of the functional significance of targeted genes with etiological validity. Based on our previous and recent findings in Akt1, the objective of this 4-year research proposal is to apply an integrated approach to study the effect of gene-gene interaction and its interaction with environmental risk factors on the alterations of neurobehavioral and neurobiological functions in mutant mice from multi-disciplinary levels. Nrg1, Akt1, and Nrg1+Akt1 heterozygous mutant mice will be used to aim at specific questions in this study. Methamphetamine-induced addiction and poly(I:C)-induced inflammation will be used as environmental insults to investigate gene-environment interaction in these mutant mice, especially in neonate and puberty. This 4-year research proposal aims at achieving the following 5 specific aims.
(1) To characterize basic behavioral functions in Nrg1, Akt1, and Nrg1+Akt1 Het mutant mice.
(2) To examine schizophrenia-related cognitive, social, and attentional functions in these mutant mice.
(3) To evaluate neurobiological and neuropathological alterations in these mutant mice.
(4) To study the effects of gene-environmental interaction during different developmental stages in these mutant mice.
(5) To explore pharmacogenetic effects of genetic deficits on treatment selection in vitro and in vivo.
Findings from this project shall contribute to our understanding of the functions of these candidate genes and how external factors in the environment or internal milieu in the body interact with genetic endowment to induce symptoms of schizophrenia. These findings will also be beneficial to screen potential pharmaceutical agents for the treatments of schizophrenia-related symptoms.
Keyword(s)
精神分裂症基因小鼠模式
Neuregulin 1
AKT1
基因與基因交互作用
基因與環境交互作用
Genetic mouse models of schizophrenia
Neuregulin 1
AKT1
gene-gene interaction
gene-environment interaction