本文選題：心臟細(xì)胞 + 鈣循環(huán)��； 參考：《浙江大學(xué)》2011年博士論文

【摘要】：鈣離子是心臟正常工作中極為重要、不可或缺的關(guān)鍵離子,深刻的影響著心臟的電興奮、肌肉收縮、信號(hào)轉(zhuǎn)導(dǎo)和基因表達(dá)等一系列生理過程,是心臟興奮收縮耦聯(lián)過程中連接電學(xué)和力學(xué)的關(guān)鍵橋梁和紐帶。目前心臟鈣循環(huán)的確切機(jī)制仍存在很多疑點(diǎn)和爭(zhēng)議。應(yīng)用數(shù)學(xué)的語言和方法對(duì)心臟鈣循環(huán)進(jìn)行建模仿真,對(duì)于探索心臟鈣循環(huán)內(nèi)在機(jī)制、研究分析心臟疾病中的鈣循環(huán)相關(guān)病理機(jī)制具有重要的理論價(jià)值和應(yīng)用價(jià)值。本文深入分析鈣循環(huán)的內(nèi)在規(guī)律和特征,建立了亞細(xì)胞水平上的微觀鈣循環(huán)模型和跨尺度復(fù)合鈣循環(huán)模型,并在鈣循環(huán)模型中引入新概念,為心臟疾病尤其是心力衰竭的機(jī)制研究提供了有力的模型支持和理論分析。本文涉及心肌細(xì)胞鈣循環(huán)的生理學(xué)基礎(chǔ),鈣循環(huán)建模仿真,病生理機(jī)制研究,主要研究?jī)?nèi)容和結(jié)論如下： (1)鈣循環(huán)模型的研究進(jìn)展和心臟鈣循環(huán)的理論知識(shí) 回顧了國際上鈣循環(huán)領(lǐng)域相關(guān)數(shù)學(xué)模型的分類和最新研究進(jìn)展,系統(tǒng)的介紹了鈣循環(huán)所依賴的肌細(xì)胞解剖結(jié)構(gòu)基礎(chǔ),心肌細(xì)胞電興奮、肌肉收縮以及在興奮收縮耦聯(lián)中起橋梁作用的鈣循環(huán)過程,著重介紹了鈣循環(huán)的局部控制理論,以及鈣離子通道特性和肌質(zhì)網(wǎng)鈣庫釋放和攝取,并詳細(xì)描述了胞內(nèi)鈣釋放事件(鈣火花和鈣波)的基本特征和內(nèi)在機(jī)制。 (2)亞細(xì)胞水平的微觀鈣循環(huán)建模 在胞內(nèi)Ca2+反應(yīng)-擴(kuò)散系統(tǒng)的基礎(chǔ)上,建立了更符合心室肌細(xì)胞微觀解剖結(jié)構(gòu)、并使用吸收邊界條件的二維時(shí)空鈣循環(huán)模型,用以模擬仿真亞細(xì)胞水平上的鈣火花、鈣波等基本鈣信號(hào),并對(duì)這些鈣信號(hào)進(jìn)行定量分析。此外,應(yīng)用本模型研究分析心臟病理?xiàng)l件下心室肌細(xì)胞內(nèi)鈣信號(hào)異常和鈣平衡紊亂現(xiàn)象,仿真結(jié)果顯示RyR簇不穩(wěn)定和/或靜息[Ca2+]i升高將促進(jìn)自發(fā)性鈣波的形成,并加速其傳播,而鈣漏流和SR鈣泵功能的影響較小,說明鈣波的演變過程是由多重因素調(diào)控的。 (3) Rogue RyR對(duì)心衰鈣循環(huán)的影響 本文將"rogue RyR"通道整合進(jìn)入二維時(shí)空微觀鈣循環(huán)數(shù)學(xué)模型,模擬仿真心衰時(shí)SR鈣庫部分卸載情況下的鈣循環(huán)特點(diǎn)。仿真結(jié)果顯示rogue RyR通道能夠以鈣夸克的形式增大靜息期SR鈣漏流；當(dāng)SR鈣庫容量減小時(shí),仍能增加自發(fā)性鈣波的發(fā)生概率；并加速鈣波的傳播。說明rogue RyR對(duì)心衰時(shí)的鈣平衡紊亂具有重要作用。在其他任何模型中通過調(diào)整RyR簇相關(guān)參數(shù)和其他離子通道都將無法模擬這種鈣循環(huán)過程,因此我們的工作提出了一個(gè)全新的鈣循環(huán)觀點(diǎn),有助于解釋心衰時(shí)鈣循環(huán)紊亂機(jī)制。 (4)跨尺度復(fù)合鈣循環(huán)模型 建立一個(gè)從亞細(xì)胞水平到細(xì)胞水平的跨尺度復(fù)合鈣循環(huán)模型,同步仿真研究心室肌細(xì)胞內(nèi)微觀鈣循環(huán)和全細(xì)胞鈣循環(huán)以及電生理特性,以及它們之間的相互影響作用。利用該復(fù)合模型,我們仿真發(fā)現(xiàn)SR腔內(nèi)鈣離子濃度改變會(huì)對(duì)亞細(xì)胞和細(xì)胞水平上的鈣信號(hào)以及細(xì)胞膜電位等細(xì)胞電生理特性產(chǎn)生影響,SR鈣庫過載則將誘發(fā)自發(fā)性鈣波,并導(dǎo)致DAD。 (5) Rogue RyR對(duì)心衰細(xì)胞的致心律失常作用 在跨尺度復(fù)合模型的基礎(chǔ)上發(fā)展了整合rogue RyR通道的心衰心室肌細(xì)胞模型,對(duì)不同rogue RyR通道密度下的微觀鈣釋放事件及所帶來的細(xì)胞水平上的鈣瞬變和電生理特性變化進(jìn)行模擬仿真。研究發(fā)現(xiàn)心衰時(shí),rogue RyR的存在會(huì)促使心室肌細(xì)胞發(fā)生DAD或觸發(fā)性動(dòng)作電位,這些觸發(fā)活動(dòng)的性質(zhì)與rogue RyR分布密度有密切關(guān)系,說明rogue RyR對(duì)心衰細(xì)胞具有致心律失常作用。
[Abstract]:Ca ~ ( 2 + ) ion is an important and indispensable key ion in the normal operation of the heart . It is a key bridge and ligament connecting electricity and mechanics in the process of cardiac muscle contraction and coupling .

( 1 ) The research progress of calcium circulation model and the theoretical knowledge of calcium circulation in the heart

This paper reviews the classification and the latest development of relevant mathematical models in the field of calcium cycling in the world , systematically introduces the anatomical structure of muscle cells , the electric excitation , muscle contraction and the calcium circulation process of the bridge in the coupling of excitation and contraction . The local control theory of calcium circulation , the calcium ion channel characteristics and the release and uptake of calcium channel of the sarcoplasmic reticulum are emphatically introduced , and the basic characteristics and internal mechanisms of intracellular calcium release events ( calcium spark and calcium wave ) are described in detail .

( 2 ) Micro - calcium cycle modeling of sub - cell level

On the basis of intracellular Ca2 + reaction - diffusion system , a two - dimensional temporal and temporal calcium cycling model is established which is more consistent with the microscopic anatomical structure of ventricular myocytes and uses the absorption boundary conditions to simulate the basic calcium signals such as calcium sparks and calcium waves at simulated sub - cell levels .

( 3 ) The influence of RyR on Ca ~ ( 2 + ) circulation in heart failure

In this paper , a mathematical model of Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) Ca ~ ( 2 + ) ~
The occurrence probability of spontaneous calcium wave can be increased when the capacity of SR Ca is decreased .
It is shown that the calcium balance in heart failure plays an important role in other models . In any other model , the calcium circulation can not be simulated by adjusting the related parameters of RyR cluster and other ion channels . Therefore , we have proposed a new viewpoint of calcium cycling , which can help explain the mechanism of calcium circulatory disturbance in heart failure .

( 4 ) Cross - scale composite calcium circulation model

A cross - scale composite calcium cycle model from sub - cell level to cell level was established , and the effects of calcium ion concentration in SR cavity on cellular electrophysiological properties such as calcium signal and cell membrane potential were studied .

( 5 ) Armogenic Effects on Heart Failure Cells Induced by rogue RyR

Based on the cross - scale composite model , the ventricular myocytes model of heart failure integrated with the RyR channel was developed . The microscopic calcium release events and the changes of calcium transient and electrophysiological properties were simulated under different densities of RyR channels .
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2011
【分類號(hào)】：R331

【共引文獻(xiàn)】

相關(guān)博士學(xué)位論文 前1條

1 吳勇;力學(xué)刺激體外培養(yǎng)頜面肌細(xì)胞及功能矯形前伸下頜后大鼠淺層嚼肌興奮—收縮單元表達(dá)變化的實(shí)驗(yàn)研究[D];四川大學(xué);2005年

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本文編號(hào)：2016358