Effects of Extravasated Serum Proteins on Human Glioblastoma Invasion

外渗血清蛋白对人胶质母细胞瘤侵袭的影响

• 批准号: 8521209
• 负责人: Hunter Reeve Underhill
• 金额: $ 11.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-02 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521209
• 关键词: Address; Adjuvant Therapy; Affect; Animal Model; Animals; Award; Behavior; Belief; Binding; Biochemical; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Brain; Cell physiology; Cells; Characteristics; Chromosomes; Clinical; Coupled; Cues; Defect; Dependence; Development; Diagnosis; Diet; Diffuse; Disease; Doctor of Medicine; Doctor of Philosophy; Employee Strikes; Environment; Etiology; Extracellular Space; Extravasation; Faculty; Genetic; Genetic Heterogeneity; Genotype; Glioblastoma; Glioma; Goals; Growth; Heterogeneity; Histology; Human; Image; Imaging Techniques; In Vitro; Infection; Infiltration; Intracranial Neoplasms; Invaded; Label; Laboratories; Laboratory Study; Large-Scale Sequencing; Lead; Leucine; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mediating; Medical Genetics; Mentors; Mentorship; Mesenchymal; Methodology; Methods; Molecular Biology; Monitor; Morbidity - disease rate; Nerve Degeneration; Neurodegenerative Disorders; Neurosurgical Procedures; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Permeability; Phenotype; Physicians; Physics; Positioning Attribute; Postdoctoral Fellow; Primary Brain Neoplasms; Proteins; Proteomics; Rattus; Recurrence; Research; Research Proposals; Residencies; Residual state; Resistance; Resources; Role; Scientific Advances and Accomplishments; Scientist; Sensitivity and Specificity; Serum; Serum Proteins; Signal Transduction; Site; Stem cells; Stroke; Surgeon; TWIST1 gene; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Transfusion; Trauma; Tumor-Derived; Universities; Vascular Endothelial Growth Factors; Washington; Work; anticancer research; bevacizumab; brain tissue; cell motility; design; experience; extracellular; improved; in vivo; inhibitor/antagonist; innovation; interest; mortality; multidisciplinary; neoplastic cell; neurological pathology; new therapeutic target; novel; overexpression; post-doctoral training; pre-doctoral; prevent; protein profiling; repaired; skills; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common and the most lethal primary brain tumor. Despite advances in a variety of therapies, survival has remained largely unchanged for more than 30 years. As a physician, I have personally witnessed the devastating morbidity and mortality associated with GBM. GBM was the principal reason that I entered Neurological Surgery. During my clinical and surgical experiences, however, I gained a deep appreciation for the lack of effect on GBM outcomes by traditional approaches. I departed my residency early with the belief that I could have a greater positive impact by making scientific advances towards understanding and then stopping GBM invasion. Through my subsequent pre- and post-doctoral studies and residency in Medical Genetics, I have steadily equipped myself with advanced skills in imaging physics, molecular biology, and proteomics. I believe I have uniquely positioned myself on a path that will enable me to use novel and multidisciplinary paradigms tempered by clinical experience to successfully approach GBM invasion. My long-term goals are to become an independent physician-scientist and to improve outcomes in patients diagnosed with GBM. My immediate goal is to complete my post-doctoral training and transition to an academic faculty position. To achieve these goals, I have designed and initiated a novel project under the guidance and mentorship of two highly productive and successful physician-scientists. Robert C. Rostomily, M.D. (mentor) leads a molecular biology laboratory that studies intracellular mechanisms of invasion in GBM. Jing Zhang, M.D., Ph.D. (co-mentor) leads a proteomics laboratory that is studying biomarkers of neurodegenerative diseases. My mentors, coupled with the unique academic and scientific environment at the University of Washington, have given me a rich and fertile setting to pursue my research, which is complementary, but unique, to their own research interests. My research proposal specifically addresses GBM invasion. The invasion of GBM into healthy brain tissues is the predominant reason for disease intractability. It is unclear why GBM tumor cells invade. However, there is compelling evidence that suggests the accumulation of specific serum proteins in the extracellular space due to disruption of the blood-brain-barrier (BBB) may govern the proliferative versus invasive phenotype. The central hypothesis of this proposal is that extravasated serum proteins (ESPs) have a direct effect on human GBM invasion. ESPs have not previously been recognized as modulators of invasion. To determine the effect of ESPs on GBM and their mechanism of action, several innovations are required. First, a novel proteomic methodology for identifying ESPs under various conditions of BBB permeability will be developed and optimized. This proteomic technique will be coupled with a novel dynamic magnetic resonance imaging (MRI) technique for measuring BBB permeability so that tissues collected for proteomic analysis can be accurately categorized. An unbiased, wide-scale technique for identifying ESPs in GBM or in any pathologic disease associated with complete or partial BBB disruption is not presently available. And finally, a state-of-the-art MRI technique known as fast bound pool fraction imaging (FBFI) will be optimized to monitor invasion of human GBM stem cells (GSCs) in an in vivo animal model. Currently available imaging techniques have been unable to capture GBM invasion in humans or in animal models of GBM. The identification of specific ESPs that actuate the invasive phenotype would deepen our understanding of GBM, while also providing new therapeutic targets that may prove more robust and/or complementary to conventional strategies. In addition, the proposed work will establish novel methodologies and technologies that have applications in a number of fields associated with neurological pathology and/or compromise of the BBB such as stroke, trauma, infection, and a variety of neurodegenerative and biochemical disorders. In summary, my unique background, established mentors, and the multitude of scientific resources at the University of Washington have provided me with an exceptional opportunity to make a significant and long- term contribution towards the improvement of outcomes in GBM. The Howard Temin Pathway to Independence Award for Cancer Research (K99/R00) will allow me to complete my post-doctoral training and provide critical support for the transition to a faculty position.

描述（由申请人提供）：多形胶质母细胞瘤（GBM）是最常见和最致命的原发性脑肿瘤。尽管有各种疗法的进步，但生存仍在很大程度上保持不变30多年。作为一名医生，我亲眼目睹了与GBM相关的毁灭性发病率和死亡率。 GBM是我进入神经手术的主要原因。然而，在我的临床和外科手术经验中，我对传统方法对GBM结果的影响缺乏影响。我很早就离开了居住，相信我可以通过对理解并停止GBM入侵的科学进步来产生更大的积极影响。通过我随后的博士后研究和医学遗传学的居留性，我稳定地配备了成像物理学，分子生物学和蛋白质组学的先进技能。我相信我已经将自己定位在一条路径上，这将使我能够使用临床经验来调整的新颖和多学科范式来成功接触GBM入侵。我的长期目标是成为独立的医师科学家，并改善被诊断为GBM的患者的结果。我的直接目标是完成我的博士后培训，并过渡到学术教师职位。为了实现这些目标，我在两个高产和成功的医师科学家的指导和指导下设计并启动了一个新型项目。 Robert C. Rostomily，医学博士（导师）领导了一个分子生物学实验室，研究了GBM侵袭的细胞内机制。 Jing Zhang，医学博士，博士（同名）领导一个正在研究神经退行性疾病的生物标志物的蛋白质组学实验室。我的导师，加上华盛顿大学的独特学术和科学环境，为我提供了一个丰富而肥沃的环境，以追求我的研究，这是对他们自己的研究兴趣的互补但独特的。我的研究建议专门针对GBM入侵。 GBM侵入健康的脑组织是疾病顽固性的主要原因。目前尚不清楚为什么GBM肿瘤细胞侵入。然而，有令人信服的证据表明，由于血脑屏障的破坏（BBB），特定的血清蛋白在细胞外空间中的积累可能控制增殖与侵入性表型。该提议的中心假设是，外部精华蛋白（ESP）对人类GBM侵袭具有直接影响。 ESP以前尚未被认为是入侵的调节剂。为了确定ESP对GBM及其作用机理的影响，需要进行几项创新。首先，将开发和优化一种新型的蛋白质组学方法，用于在BBB渗透率的各种条件下识别ESP。该蛋白质组学技术将与用于测量BBB渗透率的新型动态磁共振成像（MRI）技术结合使用，以便可以准确地分类用于蛋白质组学分析的组织。目前尚无一种无偏见的广泛的技术，用于识别GBM中的ESP或与完全或部分BBB中断相关的任何病理疾病中的ESP。最后，将优化一种称为快速池馏分成像（FBFI）的最先进的MRI技术，以监测体内动物模型中人类GBM干细胞（GSC）的入侵。当前可用的成像技术无法捕获人类或GBM动物模型中的GBM入侵。鉴定启动侵入性表型的特定ESP将加深我们对GBM的理解，同时还提供了新的治疗靶标，这些靶标可能会证明更强大和/或对常规策略进行补充。此外，拟议的工作将建立新的方法和技术，这些方法和技术在与神经病理学和/或BBB的许多领域中有应用，例如中风，创伤，感染以及多种神经退行性和生物化学障碍。总而言之，我独特的背景，已建立的导师以及华盛顿大学的大量科学资源为我提供了一个极大的机会，可以为改善GBM的成果做出重大和长期的贡献。霍华德·特姆（Howard Temin）癌症研究奖（K99/R00）将使我能够完成博士后培训，并为过渡到教师职位提供关键的支持。

项目成果

A continuous-infusion dynamic MRI model at 3.0 Tesla for the serial quantitative evaluation of microvascular proliferation in an animal model of glioblastoma multiforme.

• DOI: 10.1002/mrm.26591
• 发表时间: 2017-11
• 期刊: Magnetic resonance in medicine
• 影响因子: 3.3
• 作者: Underhill HR

Fragment Length of Circulating Tumor DNA.

• DOI: 10.1371/journal.pgen.1006162
• 发表时间: 2016-07
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Underhill HR;Kitzman JO;Hellwig S;Welker NC;Daza R;Baker DN;Gligorich KM;Rostomily RC;Bronner MP;Shendure J
• 通讯作者: Shendure J