2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659900摘要：本計畫主要的目標是在一個以果蠅為模組的系統下，研究神經修剪作用的分子機制。對於神經系統的本身功能而言，神經迴路的精確連接是必要的。神經修剪作用，對於發育中的神經系統而言是一個重塑機制，高度調控的自我毀壞程序；可選擇性的移除特定神經部位，卻不會造成神經細胞的死亡。神經修剪作用也允許神經系統以調控神經連結的方式來反應損傷或疾病的情況。因此， 神經修剪作用的任何錯誤調控也許會引發神經元的災難結果，並且造成一些神經退化性疾病的發生；例如阿茲海默症和帕金森氏症。雖然研究在發育中上游機制是如何促發神經修剪作用並且伴隨神經損傷以及神經退化疾病的看法是分歧的；但是在下游機制中，例如 ubquitin-proteasome系統是可以被預想到有很高的機會參與在這三種神經修剪作用的例子。然而，ubquitin-proteasome系統的標的蛋白參與在神經修剪作用中仍然是不知道的。我計劃使用果蠅的感覺神經元在變化期所發生的樹突修剪作用，這是一個發育的程序化過程，為一個模組系統，藉由分子和基因的研究來發現在細胞分子層級的神經修剪作用。因此，我計劃研究微管結合蛋白 Ssp4在樹突修剪作用中所扮演的角色，及其作用的分子機制。這個研究的結果可以提供更多深入的了解，在神經損傷和神經退化疾病的發病機制，並借此發展疾病治療的策略。<br> Abstract: The goal of this proposal is to uncover the underlying mechanism of neuronal pruning with Drosophila as a model system. The precise wiring of neuronal circuitry is essential for the proper function of nervous system, and that often requires neuronal remodeling to refine their connections during development. Neuronal pruning, one of the remodeling mechanisms for the developing nervous systems, is a tightly regulated self-destructive process that selectively eliminates specific parts of neuronal processes without causing cell death. Pruning also allows the nervous systems to adjust neuronal connectivity in response to injury or diseases. Thus, any mis-regulation of pruning activity may cause catastrophic results in neurons, and would contribute to the pathogenesis of certain neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, supported by the observation that gradual loss of neuronal processes occurs much earlier before actual cell death found in neurodegenerative disorders. Although the upstream triggers for the neuronal pruning during development and the pruning that follows neuronal injury and neurodegenerative diseases are divergent, it is conceivable that the downstream machinery, such as the ubiquitin-proteasome systems employed in all three cases were highly conserved. However, the protein targets for ubiquitin-proteasome systems in all three types of pruning remain unknown. The dendrite pruning of Drosophila sensory neurons during metamorphosis, which is a developmentally programmed process, is an ideal model system to investigate the cellular and molecular basis of neuronal pruning by molecular and genetic approaches. I plan to investigate the roles of Ssp4 (Patronin), a microtubule-binding protein, in dendrite pruning, and the molecular mechanism by which Ssp4 is involved during pruning. The results from this study will greatly advance our understanding on the regulation of microtubule dynamics in neuronal pruning, and provide valuable insights in understanding the pathological mechanisms and in developing therapeutic strategies of neuronal injury and neurodegenerative disorders.