基於數學模型對新生大鼠心肌細胞內鈣離子/鈣調素蛋白激酶II活性調控之探討

Abstract

鈣離子/鈣調素蛋白激酶Ⅱ的複雜動動力學一直以來都是一個無論於疾病醫學或生理學皆炙手可熱的研究主題，這是由於它在細胞信號傳遞中的關鍵角色，特別是在心臟生理學方面。 本研究提出了一種新穎的方法，通過整合四種不同的數學模型架構，這在電腦模擬大鼠心臟細胞的領域中仍然相對稀缺，具有獨特的特點。 此篇論文的電腦模擬是為了與約翰霍普金斯大學所做的新生大鼠心臟細胞中鈣離子/鈣調素蛋白激酶Ⅱ活性檢測的實驗數據進行比對探討。 實驗數據中，有控制組以及加了異丙腎上腺素(Isoproterenol)的對照組，不過缺乏了加入活性氧類(Reactive Oxygen Species, ROS)的鈣離子/鈣調素蛋白激酶Ⅱ活性實驗數據。 因此，此篇論文的模擬進行了與控制組及對照組實驗數據的比對探討，也進行了加入活性氧類後鈣離子/鈣調素蛋白激酶Ⅱ活性的模擬預測。 因為現有文獻在研究大鼠心肌細胞中鈣離子/鈣調素蛋白激酶Ⅱ活性探討的數學建模相當稀少，因此突顯了此篇模擬方法的新穎性。通過綜合和適應各種數學建模技術，我們的目標是提供對新生大鼠心室肌細胞中鈣離子/鈣調素蛋白激酶Ⅱ活性的變化有更全面的理解。多個模型的整合使我們能夠捕捉鈣離子/鈣調素蛋白激酶Ⅱ在不同條件下的微妙的活性狀態變化。由於缺少了大鼠心肌模型中鈣離子/鈣調素蛋白激酶Ⅱ活性探討的文獻，此篇研究借鑒Morotti等人的小鼠心室肌細胞模型以及其他模型的建模方法，我們整合並且進行了在新生大鼠背景下的模擬應用。這種全面的方法不僅提高了我們發現的可靠性，還有助於填補有關大鼠心臟細胞模擬的文獻中的短缺。 我們的研究結果揭示了在新生大鼠心室肌細胞中調節CaMKII的多面性機制，為細胞信號通路提供了有價值的見解。本研究中各種建模技術的融合標誌著在物種特定背景下揭示CaMKII動態複雜性的一個重要步驟。隨著數學建模繼續在心臟研究中發揮關鍵作用，本研究為未來旨在闡明在不同實驗環境中CaMKII活性變化的探索鋪平了道路。

The intricate regulatory dynamics of CaMKII within cardiac myocytes constitute a central focus in contemporary research, given their pivotal role in cellular signaling and cardiac physiology. This study employs a computational framework to explore CaMKII activity by integrating four distinct modeling frameworks: excitation-contraction coupling, beta-adrenergic signaling pathway, CaMKII autoregulation, and oxidative regulation. Our model is constructed based on the Morotti-Grandi mathematical model of mouse cardiomyocytes with beta-adrenergic receptors, the rat cardiomyocyte model by Korhonen et al., a refined CaMKII activation model inspired by Chang et al., and the incorporation of oxidative CaMKII states as proposed by Christensen et al. By coupling these models with calcium transients, we scrutinize variations in CaMKII activity under diverse conditions, including different pacing frequencies and durations, isopropanol and super oxide stimulations. The model parameters are rigorously constrained using experimental data on CaMKII activity in neonatal rat ventricular myocytes, conducted at Johns Hopkins University and supplemented by relevant literature. By integrating multiple models, our approach captures nuanced intricacies in CaMKII regulation, allowing for the analysis of the intricate interplay of CaMKII-mediated processes. Leveraging insights from the mouse ventricular myocyte model and other relevant sources, we extend the applicability of computational simulations to the neonatal rat context. Our findings offer valuable insights into the multifaceted regulatory mechanisms governing CaMKII, and the amalgamation of diverse modeling techniques in this study represents a significant advancement in unraveling the complexities of CaMKII dynamics within a species-specific context. As computational modeling continues to play a crucial role in advancing cardiac research, our study not only contributes to the current understanding of CaMKII dynamics but also lays the foundation for future investigations seeking to elucidate the intricacies of CaMKII activity in various experimental settings.