Control Issues in Cancer Therapy

本建议概述的研究目标有两个方面。首先，我们打算探索应用现有的控制遗传学知识来推进癌症治疗的可能性；其次，我们打算在控制方面取得根本性的成果，以解决癌症相关研究中出现的一些独特问题。提出的研究是由私家侦探的动机他在美国国家癌症研究所培训基金的支持下，作为生物信息学实习生，在两年的时间里，他积累了丰富的教学和研究经验。在培训过程中，p.i.p认识到，癌症是由多细胞组织中调节细胞数量的控制系统发生故障引起的，从而阻止了肿瘤等不良生长的发生。此外，私家侦探和合作私家侦探。我们坚信，工程文献中经过时间考验的控制技术可以发挥作用，并进一步发展，以获得有用的癌症治疗指南。已经获得了有希望的排除结果，表明了一个明确的研究方向。具体来说，我们与我们的分子生物学同事Michael Bittner（仅与国家人类基因组研究所（NHGRI）合作，目前与T翻译基因组研究所（TGEN）合作）开发了一个框架，用于模拟受外部干预的遗传调控网络，并使用它来应用最优控制策略来减缓转移性黑色素瘤的进展。本文所使用的模型是带有外部控制的P概率布尔网络模型（PBN），我们证明了它是受控马尔可夫链的一种特殊情况。这使得应用标准和最优控制技术（如动态P测井）成为可能，并使我们能够进行这一概念验证研究。受这一成功和我们在控制理论方面的丰富经验的激励，我们开始了一项旨在模拟癌细胞系受到不同剂量电离辐射时行为的扩展研究。这项研究是与国家癌症研究所（NCI）的Albert Fornace实验室合作进行的，这是我们的主要数据来源。利用这些辐射研究的基因表达数据，我们打算建立PBN模型，我们希望这将使我们能够一直寻找增加细胞在辐射下死亡的能力。一种叫做p53的基因。这是一个合理的控制目标，也具有生物学意义，因为(i)细胞受到辐射会受到DNA损伤；（ii）如果DNA受损的细胞被允许复制，就会导致癌症；（iii） p53基因的功能之一是确保细胞分裂的DNA复制阶段不会发生，除非亲本细胞的DNA受损。rst epaired。我们对辐射实验的基因表达数据的初步评估显示了明显的di。功能p53细胞系与功能p53细胞系之间的差异。p53保证。因此，我们计划追求的研究路线似乎是一条非常有前途的路线。其中一个合伙人。从工程文献到实际应用中，这一建议在开拓信号处理技术的应用方面发挥了重要作用。在基因组学领域，而另一个合作pi。很长一段时间以来，联合国一直没有对《控制》领域作出原创贡献。对拟议研究成功的乐观部分源于这样一个事实，即私家侦探在与合作私家侦探的每次合作中都取得了成功。都是过去的事了。此外，让我们的分子生物学合作伙伴Michael Bittner和Albert Fo充分参与这项研究，将大大有助于确保所开发的结果具有生物学意义。我们在癌症治疗方面取得的任何进展，即使是细胞系，都必然会对社会产生深远的影响。使用细胞系的成功干预研究是随后动物研究和最终临床试验的先导，然后才批准在一般人群中使用特定癌症治疗。因此，我们在这项研究中取得的任何重大进展都将不仅影响目前的癌症治疗，而且影响未来几年的癌症治疗。好处。这将是人类生命在未来被拯救的条件

The objectives of the esea ch outlined in this proposal a e two fold.First,we intend to explo e thepossibility of applying existing cont ol theo etic knowledge to advance the cause of cancer therapy;andsecond,we intend to develop fundamental esults in control theo y to address some of the unique p oblemsthat arise in cancer related esearch.The proposed esearch is motivated by the P.I.'s didactic and esearchexperiences du ing his two-year stint as a Bioinformatics T ainee supported by a National Cancer InstituteT aining Grant.In the course of this training,the P.I.has ealized that the disease Cancer is causedby a b eakdown in the control system that egulates the cell numbe s in a multicellula o ganismand p events undesirable g owths such as tumo s from developing.Furthermo e,the P.I.and the co-P.I.'s strongly believe that the time-tested cont ol techniques from the engineering literature could beha nessed,and further developed fo obtaining useful guidelines in cancer therapy.P omising p elimina y esults indicating a clea esea ch direction have already been obtained.Specif-ically,in collabo ation with ou molecula biologist colleague,Michael Bittner (fo merly with the Na-tional Human Genome Resea ch Institute (NHGRI),cur ently with the T anslational Genomics Institute(TGEN)),we developed a f amework for modeling genetic regulatory networks subject to external in-terventions and used it to apply optimal control st ategies to slow down the p ogression of metastaticmelanoma.The pa ticula modeling f amewo k used was the P obabilistic Boolean Netwo k (PBN)modelwith external controls,which we showed to be a special case of a Cont olled Markov Chain.This madeit possible to apply standa d optimal control techniques such as Dynamic P og amming and enabled usto carry out this proof of concept study.Motivated by this success and our extensive experience in Control Theory,we have embarked on anexpanded study aimed at modeling the behaviour of cancer cell lines when they are subjected to variousdoses of ionizing adiation.This study is being carried out in collaboration with Albert Fornace 's labo-ato y at the National Cancer Institute (NCI),which is our prima y data sou ce.Using gene exp essiondata from these adiation studies,we intend to build PBN models that we hope will enable us to look foways to increase the capacity of cells to die upon adiation when they are de .cient in a gene called p53.This is a easonable control objective that also makes biological sense since (i)cells subjected to radiationundergo DNA damage;(ii)if the cell with DNA damage is allowed to eplicate,cancer can esult;and(iii)one of the functions of the gene p53 is to ensure that the DNA eplication stage of cell division doesnot occu unless the damaged DNA of the parent cell is .rst epaired.Ou initial assessment of geneexpression data f om radiation experiments has evealed marked di .erences between the cell lines withfunctional p53 versus those with de .cient p53.Consequently,the line of esea ch that we a e planningto pursue appea s to be a very p omising one.One of the co-P.I.'s of this proposal was instrumental inpioneering the application of signal p ocessing techniques from the engineering literature to the .eld ofgenomics while the other co-P.I.has had a long histo y of o iginal contributions to the Controls .eld.Optimism about the success of the proposed research partially stems from the fact that the P.I.has hadsuccessful esea ch collabo ations with both the co-P.I.'s in the past.In addition,keeping our moleculabiologist collabo ato s Michael Bittner and Albert Fo nace fully involved in the esea ch will go a longway towards ensuring that the esults developed emain biologically meaningful.Any advance that we make in pursuing cancer therapy,even fo cell lines,is bound to have a profoundimpact on society.Successful intervention studies using cell lines are the precursors that lead to subsequentanimal studies and ultimately clinical trials,befo e the pa ticula cancer treatment is approved fo useon the general population.Thus,any signi .cant ground that we b eak in the cou se of this research willimpact cancer treatment not only fo the present time,but also fo years to come.The bene .t will be interms of human lives that are saved down the oad.2