果蠅神經生物實驗室
DROSOPHILA NEUROBIOLOGY LAB
果蠅神經生物實驗室
National Yang Ming Chiao Tung University
RESEARCH INTERESTS
BRAIN AGING AND NEURONAL CONTRIBUTION TO ANIMAL LIFESPAN
Many studies have suggested, while aging is a time-dependent biological process, it can be modulated by specific genetic programs acting at designed chronological ages. Moreover, changes of gene expression levels likely play paramount roles in the aging process and could potentially serve as biomarkers of physiological decline and disease status. Recently several hallmarks of aging have been discussed, such as the genomic instability, epigenetic modifications, failure of proteostasis, deregulated nutrient sensing, and mitochondria damages. However, the molecular machinery underpinning aging progression remains largely unknown. In this proposal, we use the model organism, Drosophila melanogaster, to study aging-related phenotypes and aging progression of the central nervous system. Systematic temporal profiling of gene expressions in normal fly brain samples and animals with altered life expectancy via the advanced NGS technology will allow us to identify aging-related biomarkers and study the key effector mechanisms. With the continuously expanding genetic toolkits for the Drosophila research, various phenotypic analyses and mechanistic studies can be creatively implemented. In addition, we also like to explore the physiological changes of specific neuronal/glial types along animal lifespan. From our preliminary results of brain aging-related gene expressions, we found members of the small heat shock protein (sHSP) family are gradually up-regulated during aging and their activities alter the organisms’ life expectancy. In this proposal, we aim to further characterize the molecular functions of sHSPs in the context of aging machinery. Lastly, since aging is closely associated with the onset and progression of distinct neurodegenerative diseases, we also plan to explore the neuroprotective capability conferred by the aging-associated genes identified in this project.
生物老化被認為是一種隨著時間進行的自然現象，但是許多研究發現透過基因操作可以操作生物的老化速度，並 且特定基因表現的時間變化也被視為是老化的重要生物指標，甚至生理機能的改變以及疾病的發生也可以由基因 表現的改變而被發現，目前相關研究認為造成老化的因素有: 基因體的不穩定、表觀遺傳的改變、體內蛋白質平 衡失調、營養訊號感知下降以及粒線體受損等等，然而，老化的現象在分子機制還有許多不明瞭的地方。我們將 使用模式生物果蠅來了解老化的現象以及老化在中樞神經系統所扮演的角色。
利用次世代定序技術，我們將系統性對不同年齡果蠅中樞神經系統的基 因表現做詳盡的分析，並著重於尋找與老化相關的生物指標基因，再透 過不同的基因遺傳調控方法去觀察老化造成的各種表徵，進而探討老化 的關鍵機制。此外，我們也會探討不同種類的神經細胞及膠細胞在個體 老化的功能變化，但是這個目標將需要發展新的檢驗方法。最後，我們 先前的研究已經發現有一群熱休克蛋白基因的表現量會隨著果蠅老化大 幅度上升，並且已有研究指出其對果蠅壽命的調控扮演重要的角色。我 們將進一步探討其在老化機制中所扮演的功能，由於神經退化性疾病的 發生和發展往往和老化有高度相關，我們也將從與老化相關的基因中， 尋找可能具有神經系統保護功能的基因。並驗證其是否具有延緩或阻止 神經退化性疾病進行的功能。
TEMPORAL BEHAVIOR OF NEURAL STEM CELLS
The complexity of central nervous system is predominantly attributed by the highly diverse neuron types derived from a confined number of neural stem cells. During the course of neurogenesis, each distinct neural stem cell gives rise to a distinct set of diverse neurons. The neurons sequentially derived from a given neural stem cell are collectively called a neuronal lineage. To learn the developmental processes and molecular signatures of distinct neural stem cells, Drosophila melanogaster is an excellent in vivo model system. Using Drosophilia genetics, several mosaic labeling techniques capable of marking specific neural stem cells as well as their progeny have been invented to serve the purposes. However, there are limitations in terms of the specificity of neuronal lineages labeled and the efficiency of lineages that can be examined in one set of experiment. To circumvent these limitations, we determine to design and build a new series of lineage-oriented genetic tools. These newly developed tools and the innovative mosaic labeling approach will allow us to perform the “targeted” lineage(s) analysis in great efficiency. Concurrent systematic characterization of every single neurons produced from multiple targeted neuronal lineages will be feasible, expediting our understanding the lineage-orchestrated Drosophila brain.
複雜的中樞神經系統是由多種形態的神經細胞所組成，而多樣的神經細胞都是由固定數量的神經 幹細胞所分化而成。從同一神經幹細胞接續分化出的神經細胞統稱為神經譜系，利用在果蠅模式 生物中開發的遺傳標定技術(genetic mosaic labeling techniques) ，我們可以標記特定的神經 幹細胞及衍生的神經細胞譜系，進而了解各種神經幹細胞發育的過程和其分子機制
DROSOPHILA AVATARS OF HUMAN CANCERS – MECHANISTIC STUDIES OF TUMOR BIOLOGY AND DRUG SCREENING PLATFORM FOR ANTI-CANCER TREATMENT
腫瘤的形成並非源自單一細胞因子和環境，隨著對於腫瘤形成及發展的相關研究日益增加，更有效的抗癌藥物及標靶治療 已被陸續開發，然而現今在腫瘤治療上仍然沒有最完善的治療方式。利用果蠅作為實驗模式生物已經成功了解許多有關致 癌基因和腫瘤抑制子的生理機制，近期的研究更指出果蠅模式系統可以作為有實質應用價值的藥物篩選平台。我們將利用 果蠅模式生物研究腫瘤的形成及發展。 現今，許多研究已經從人類檢體中發現多種與腫瘤相關的突變，然而誘發腫瘤突變的形成尚未明瞭，除此之外，闡明腫瘤 誘發因子在特定組織器官中的致癌能力以及專一的腫瘤基因體(不同的腫瘤類型和病人有多樣的突變型態)在技術上是具 有挑戰性且需花費大量的準備時間。如果以果蠅實驗模型來研究單一致癌基因或是了解許多致癌及抑癌基因間的交互作用 上都有極大的優勢，更重要的是在果蠅模型上可以建立與人類癌症相對應的突變基因背景，讓果蠅成為具有更接近人類腫 瘤特徵且有效率的藥物篩選平台。我們與生物資訊學家組成團隊，著眼於建立果蠅癌症模型來研究造成腫瘤的驅動突變並 進行抗癌藥物篩選，希望此研究能夠提供個人化的精準醫療和廣泛的癌症治療策略。