發(fā)布時間：2018-05-12 08:45

  本文選題：癌癥 + 干細胞　； 參考：《浙江大學(xué)》2011年博士論文

【摘要】：隨著醫(yī)學(xué)的不斷進步,醫(yī)療衛(wèi)生事業(yè)的不斷發(fā)展,許多疾病都得到了控制甚至完全消滅。但有些疾病的研究卻變得更加迫切,尤其是癌癥。盡管在很早以前就有癌癥的報道,對該疾病的大量研究還是從大約半個世紀前開始的�？梢哉f,最早的癌癥研究應(yīng)該屬于醫(yī)學(xué)領(lǐng)域,因為對該病的認識嚴重不足,所以研究的重點都放在了臨床的診斷與治療上；而如今,隨著交叉學(xué)科的快速發(fā)展,數(shù)學(xué)和工程的方法也逐步應(yīng)用于癌癥領(lǐng)域,因此,癌癥研究也就成為了生物醫(yī)學(xué)工程領(lǐng)域的一個課題。而臨床、試驗數(shù)據(jù)的海量化,實驗設(shè)備和生化試劑的成本級數(shù)遞增,也迫切需要有一種更高效、更廉價、更易重復(fù)的方法出現(xiàn)。于是,數(shù)學(xué)腫瘤學(xué)就應(yīng)運而生了。雖然在模型建立和驗證時,仍然十分依賴于臨床實驗數(shù)據(jù),但是數(shù)學(xué)腫瘤學(xué)極大的推動了該課題的發(fā)展,不但節(jié)約了人力、物力、財力,而且在海量數(shù)據(jù)統(tǒng)計分析、發(fā)病機理和疾病發(fā)展預(yù)測方面,都發(fā)揮了重大作用。也正因為如此,之前不被看好的數(shù)學(xué)腫瘤學(xué),才在近年來逐漸被臨床醫(yī)生和實驗研究人員接受。 對癌癥的建模應(yīng)該是多尺度的,目前大致可以分為三層：分子層次,細胞層次和組織層次。分子層次包括基因轉(zhuǎn)錄和蛋白表達、信號通路的信號傳遞等,對這些過程的建模主要是用一系列的化學(xué)反應(yīng)平衡方程來表示,在給定初始值和測定參數(shù)值的情況下,分析各個成分隨時間的變化情況。細胞層次描述單個細胞的特性,包括生長、休眠或凋亡,分裂速度、消耗營養(yǎng)的快慢,是否進行分化等,主要通過分子層次的仿真結(jié)果來判定。組織層次包括細胞間的相互作用,細胞與細胞周圍的生長因子、激素或養(yǎng)分之間的相互作用,建模的方法是用一系列的常微分、偏微分方程組來描述細胞的運動、營養(yǎng)的衰減吸收等過程。根據(jù)研究目的的不同,腫瘤模型也可以分為一維、二維和三維等不同的層次：一維模型快速而經(jīng)濟,能方便的給出各種成分隨時間的變化情況；二維三維模型能給出各個成分的空間分布情況,有利于更直觀和精確的了解發(fā)展過程,其缺點是計算量大,對計算機和數(shù)值算法的要求較高。 哲學(xué)上說,任何事物的發(fā)展是由內(nèi)因和外因共同作用的。這句話也適用于癌癥。盡管最初的研究傾向于強調(diào)癌癥發(fā)生的內(nèi)因性,認為基因突變是其發(fā)生的原因；近些年來,越來越多的研究表明,外部因素也極重要的影響著癌癥的發(fā)生。特別的,在本研究中談及的外部因素主要是腫瘤微環(huán)境,也就是腫瘤組織周圍的各種細胞成分與非細胞成分的整體。與正常細胞一樣,腫瘤細胞也需要有營養(yǎng)物質(zhì)、生長因子和成纖維細胞等成分,為其存活和增生提供必要的能量、信號和支架等。因此,腫瘤的生長過程可以說與腫瘤微環(huán)境之間的相互作用是從不間斷的。讓我們試想,假如能夠通過數(shù)學(xué)建模的方法來定量描述這些相互作用,并能通過計算機仿真,預(yù)測某個特定腫瘤會如何發(fā)展,以及該用什么治療方法去控制甚至是消除,那么,癌癥或許就沒那么可怕了。事實上,這就是本研究的最終目標。 論文完成的主要研究工作包括： 一、數(shù)學(xué)腫瘤學(xué)的進展和理論框架研究 系統(tǒng)的總結(jié)和分析了目前數(shù)學(xué)腫瘤學(xué)的研究進展。首先介紹了癌癥研究發(fā)展史,給出癌癥的定義、分類以及目前的臨床統(tǒng)計情況。其次給出數(shù)學(xué)腫瘤學(xué)的定義,并探討了相關(guān)數(shù)學(xué)模型的發(fā)展過程和未來的發(fā)展方向。針對癌癥的不同發(fā)展階段,我們總結(jié)了相應(yīng)數(shù)學(xué)模型的建立過程,并給出典型例子來詳細說明。然后介紹了目前在癌癥研究領(lǐng)域處于領(lǐng)先地位的各個小組,并大致描述并總結(jié)了他們所做工作的重點和取得的成果。最后提出了一個實驗手段與數(shù)學(xué)方法緊密結(jié)合的多尺度癌癥建模的理論框架。 二、乳癌的數(shù)學(xué)建模與仿真研究 作為數(shù)學(xué)腫瘤學(xué)的實際應(yīng)用,我們研究了人體乳癌發(fā)生、發(fā)展和藥物治療的過程。我們首先描述了乳癌細胞、干細胞微環(huán)境、內(nèi)皮生長因子受體信號通路和藥物成分之間的關(guān)系,然后用一組微分方程組的區(qū)間模型來定量計算乳癌發(fā)展過程中各個成分的變化情況。本文首次將腫瘤干細胞微環(huán)境的作用考慮到乳癌的仿真模型中來。仿真結(jié)果表明,我們的數(shù)學(xué)模型十分穩(wěn)定,能很好的考慮干細胞、微環(huán)境、信號通路以及藥物作用,與臨床實驗觀察的結(jié)果十分接近。最后,我們也利用該模型進行了一系列的理論治療仿真,并提示了干細胞微環(huán)境在臨床治療上的重要意義。 三、骨髓增生異常綜合癥的數(shù)學(xué)建模與仿真研究 在分析和總結(jié)骨髓增生異常綜合癥的臨床數(shù)據(jù)后,我們提出了一種簡化的區(qū)間模型來描述該病癥。該模型主要包括骨髓和外周血兩個區(qū)間,每個區(qū)間內(nèi)又包括正常的和異常的兩類細胞,處于骨髓內(nèi)的干細胞通過分化形成各種血細胞進入到外周血中,而外周血中細胞數(shù)量的多少反過來又影響干細胞的增生和分化。在歸納和抽象臨床實驗知識的基礎(chǔ)上,我們首次將干細胞龕的概念引入到該病的數(shù)學(xué)建模中來。我們用一組常微分方程來描述該病癥的發(fā)生發(fā)展過程,并通過提出一種可能的治療方法來控制甚至治愈該病。模型仿真結(jié)果顯示,我們的模型簡單、穩(wěn)定,卻能很好的闡釋MDS可能的發(fā)生機制和并提供可能的治療方案。
[Abstract]:With the continuous progress of medicine and the continuous development of medical and health services, many diseases have been controlled and even completely eliminated. But the research of some diseases has become more urgent, especially cancer. Despite the reports of cancer early on, a large number of studies on the disease began about half a century ago. Cancer research should be in the field of medicine, because the understanding of the disease is seriously inadequate, so the focus of the research is on clinical diagnosis and treatment. Now, with the rapid development of interdisciplinary, mathematical and engineering methods are gradually applied to the field of cancer. Therefore, cancer research has become the field of biomedical engineering. A subject in which the clinical, experimental data is massive, the cost progression of experimental equipment and biochemical reagents is increasing, and there is an urgent need for a more efficient, cheaper, and more repeatable method. Oncology has greatly promoted the development of the subject. It not only saves manpower, material and financial resources, but also plays a major role in the statistical analysis of massive data, the pathogenesis and the prediction of disease development. Accept.
The modeling of cancer should be multiscale. At present, it can be divided into three layers: molecular level, cell level and organization level. Molecular level, including gene transcription and protein expression, signal transduction, and so on. The modeling of these processes is mainly expressed by a series of chemical reaction equilibrium equations, given initial values and measurements. In the case of the fixed parameter, the changes of each component with time are analyzed. The cell level describes the characteristics of a single cell, including growth, dormancy or apoptosis, the speed of division, the fast and slow consumption of nutrients, or whether the differentiation is carried out, mainly by the simulation results of the molecular level. The organization level includes intercellular interaction, cell and fine. The interaction of growth factors, hormones or nutrients around the cell. The modeling method is to use a series of ordinary differential and partial differential equations to describe the process of cell movement and nutrient attenuation absorption. According to the different purpose of the study, the tumor model can be divided into one dimension, two dimension and three dimensions, and the one dimension model is fast and fast. The economy can easily give the change of various components with time. The two-dimensional three-dimensional model can give the spatial distribution of each component, which is beneficial to the more intuitive and accurate understanding of the development process. Its disadvantage is that the computational complexity is large and the requirements for computer and numerical algorithms are higher.
Philosophically, the development of everything is combined with internal and external factors. This sentence also applies to cancer. Although the initial research tends to emphasize the internal causes of cancer, it is considered the cause of the mutation; in recent years, more and more studies have shown that the external factors are also very important to the occurrence of cancer. In addition, the external factors involved in this study are mainly the tumor microenvironment, that is, the various cellular components and non cellular components around the tumor tissue. Like the normal cells, the tumor cells also need nutrients, growth factors and fibroblasts to provide the necessary energy, signals and branches for their survival and proliferation. Therefore, the interaction between the tumor growth process and the tumor microenvironment is uninterrupted. Let us try to imagine how these interactions can be described quantitatively by mathematical modeling and can be simulated by computer to predict how a particular tumor will develop and what treatment should be used to control it. Even if it is eliminated, then cancer may not be so terrible. In fact, this is the ultimate goal of this study.
The main research work completed in this paper includes:
First, research on the progress and theoretical framework of mathematical oncology
The research progress of mathematical oncology at present is summarized and analyzed. First, the history of cancer research and development, definition, classification and clinical statistics of cancer are given. Secondly, the definition of oncology is given, and the development and future direction of the mathematical models are also discussed. In this stage, we summarize the process of establishing the corresponding mathematical model and give a typical example. Then we introduce the groups that are in the leading position in the field of cancer research, and describe and summarize the focus and achievements of their work. Finally, we put forward an experimental method and a mathematical method. A theoretical framework for multi-scale cancer modeling.
Two, mathematical modeling and Simulation of breast cancer
As a practical application of mathematical oncology, we studied the process of human breast cancer, development and drug treatment. We first described the relationship between breast cancer cells, stem cell microenvironment, endothelial growth factor receptor signaling pathway and drug components, and then used a group of differential equations to quantify the development of breast cancer. In this paper, the role of the tumor stem cell microenvironment is considered in the simulation model of breast cancer for the first time. The simulation results show that our mathematical model is very stable and can consider the stem cells, microenvironment, signal pathways and drug effects very well. Finally, we are in close proximity to the results of clinical observation. A series of theoretical treatment simulations are also carried out using this model. It also indicates the importance of stem cell microenvironment in clinical treatment.
Three, mathematical modeling and Simulation of myelodysplastic syndrome.
After analyzing and summarizing the clinical data of myelodysplastic syndrome, we present a simplified interval model to describe the disease. This model mainly includes two intervals of bone marrow and peripheral blood, each of which includes two types of normal and abnormal cells, and the stem cells in the bone marrow form various blood cells through the differentiation. In the peripheral blood, the number of cells in the peripheral blood in turn affects the proliferation and differentiation of stem cells. On the basis of induction and abstract clinical knowledge, we introduce the concept of stem cell niche to the mathematical modeling of the disease for the first time. We use a group of ordinary differential Cheng Lai to describe the occurrence and development of the disease. A possible treatment to control or even cure the disease has been proposed. The model simulation results show that our model is simple and stable, but it can explain the possible mechanisms of MDS and provide possible treatment options.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R311

【參考文獻】

相關(guān)期刊論文 前3條

1 邱林;;骨髓增生異常綜合癥發(fā)病機制和臨床治療的研究進展[J];臨床腫瘤學(xué)雜志;2009年12期

2 宋奇思;;癌癥綜合治療新進展[J];醫(yī)藥與保健;2006年11期

3 趙淵源;李春艷;;Wnt與Notch信號通路的串話與腫瘤發(fā)生、發(fā)展的關(guān)系[J];國際病理科學(xué)與臨床雜志;2010年03期

，

本文編號：1877938