2012-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659904摘要：本計畫的主要目標是要在一個以果蠅為模組的系統下，發現神經修剪作用的基礎機制。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，藉由觀察到神經細胞逐步失去神經突觸早於細胞死亡的時間，來支持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。雖然研究在上游機制是如何誘發神經修剪作用在發育過程中，及其是如何促發神經修剪在神經損傷之後以及神經退化疾病的看法是分歧的；但在下游機制中，這三種神經修剪作用的例子皆需要泛素蛋白酶體系統 (ubquitin-proteasome system) 的參與。然而，在這三種神經修剪作用的例子中，泛素蛋白酶體系統如何調控和運作的分子機制仍然是不清楚的。我計劃使用果蠅的感覺神經元在蛹化時期所發生的樹突修剪作用，這是一個計劃性的神經發育過程，作為一個模組系統，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。我的研究已經定義了一個新的IK2/Snp-F訊號傳遞路徑和一些基因對於在果蠅神經系統中的樹突修剪作用是必須的。另外，我也發現Spn-F並不只直接和一個蛋白酶體的一個次單元Rpn2交互作用，但是同時顯 示在樹突修剪作用中和Rpn2有強烈的基因的交互作用。因此，我計劃透過研究Rpn2和Spn-F/Rpn2在樹突修剪作用中的交互關係來發現蛋白酶體在剪切修飾作用中的規則；並且更進一步的研究在神經樹突修剪作用中，蛋白酶體活性的機制是如何在次細胞的區隔中被調控的。這個研究的結果可以提供更多深入的了解，在於神經損傷和神經退化疾病的發病機制，並研發出治療的方式。<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 molecular mechanisms how the ubiquitin-proteasome systems are regulated and operate in all three types of pruning remain unknown. I plan to use the dendrite pruning of Drosophila sensory neurons during metamorphosis, which is a developmentally programmed process, as a model system to investigate the cellular and molecular basis of neuronal pruning by molecular and genetic approaches. I have identified a novel Ik2/Spn-F signaling pathway and several genes that are essential for dendrite pruning in Drosophila’s nervous system. In addition, I also found that Spn-F not only interacts with Rpn2, a subunit of proteasome complex, directly, but also shows strong genetic interaction with Rpn2 in dendrite pruning. Thus, I plan to investigate the roles of proteasomes in pruning through studing the function of Rpn2 and the Spn-F/Rpn2 interaction in dendrite pruning, and further to investigate the mechanisms whether and how the proteasomal activity is regulated in subcellular compartments during pruning. The results of this study will provide valuable insights in understanding the pathological mechanisms and in developing therapeutic strategies of neuronal injury and neurodegenerative disorders.神經網絡修剪蛋白？體神經退化neuronal pruningneurodegenerationproteasome