The effects of dexamethasone on tumor and microglial cells in glioma

地塞米松对胶质瘤肿瘤和小胶质细胞的影响

• 批准号: 8546310
• 负责人: Terreia Sutton Jones
• 金额: $ 14.28万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2013-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546310
• 关键词: Accounting; Address; Adrenal Cortex Hormones; Advisory Committees; Affect; Alkylating Agents; Applications Grants; Award; Brain Neoplasms; CXCL12 gene; CXCR4 gene; Cancer Biology; Cell Proliferation; Cells; Clinical; Clinical Research; Coculture Techniques; Collaborations; Commit; Cytotoxic Chemotherapy; DNA Damage; Data; Data Set; Development Plans; Dexamethasone; Disease; Dose; Edema; Effectiveness; Elements; Ensure; Environment; Equipment; Excision; Experimental Models; Extramural Activities; Fellowship; Funding; Gene Expression; Gene Proteins; Genes; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Health Sciences; Immunohistochemistry; In Vitro; Inflammatory; Ionizing radiation; Knowledge; Laboratories; Lead; Left; Maintenance; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Manuscripts; Measures; Medical center; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Microglia; Modeling; Molecular; Mus; NCI Center for Cancer Research; Neurologic; Neurologic Symptoms; Neurosurgeon; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacy facility; Platelet-Derived Growth Factor; Population; Postoperative Period; Primary Brain Neoplasms; Process; Proliferating; Publications; Publishing; Radiation; Research; Research Infrastructure; Research Support; Residencies; Resources; Saint Jude Children' s Research Hospital; Science; Scientist; Secure; Stromal Cells; Symptoms; Techniques; Tennessee; The Cancer Genome Atlas; Therapeutic; Time; Training; Universities; Visit; Work; career development; cell type; clinically relevant; in vitro Model; in vivo; inhibitor/antagonist; insight; leukemia; meetings; mouse model; neoplastic; neoplastic cell; neuro-oncology; preclinical study; professor; programs; response; standard of care; success; symptomatic improvement; temozolomide; tool; tumor

DESCRIPTION (provided by applicant): The candidate: Dr. Terreia Jones is an Assistant professor in the Department of Clinical Pharmacy at the University of Tennessee Health Science Center (UTHSC). She completed her residency training in clinical pharmacy practice at the VA Medical Center (Memphis, TN) and her fellowship training focused in the pharmacogenetics of anti-leukemia therapy at St. Jude Children's Research Hospital (Memphis, TN). Dr. Jones is now building a research program focused in neuro-oncology under the mentorship of a world-renowned brain cancer biologist and neurosurgeon, Dr. Eric C. Holland. The goals of Dr. Jones' career development are centered on her desire to become a successful clinical brain cancer scientist which include: establishing strong collaborations in the neuro-oncology field, 2) publishing high-impact publications relevant to brain cancer, and 3) securing extramural funding to support her research. Key elements of her research career development plan include extended visits to Memorial Sloan Kettering Cancer Center to acquire experimental techniques in her mentors laboratory; attending and presenting at recurring institutional seminars (at the University of Tennessee Health Science Center, St. Jude Children's Research Hospital and Memorial Sloan Kettering); and frequent meetings with her advisory committee that consists of well-establish brain cancer scientists for guidance and support. The research resulting from this award will be presented at scientific meetings annually and is expected to generate a minimum of 4 - 8 manuscripts over the tenure of the award and lead to a successful R01 submission. Environment: The UTHSC has committed to provide the necessary infrastructure to nurture Dr. Jones' career development and has provided an excellent environment in which to train, both physically in the form of exceptional lab space and equipment. There are a number of relevant seminars between the UTHSC and St. Jude campuses that will enhance her knowledge in cancer biology. She has the overwhelming support of her administration, working under a Department Chair and Dean who embrace competitive science in clinical pharmacy. The University's support has been integral in helping Dr. Jones establish a fruitful relationship with Dr. Holland thus far. As detailed in the applicatin, the Dean and Chair both commit to protecting 75% of her time to dedicate to her career development. Dr. Larry Pfeffer (co-mentor and Director of the UTHSC Center for Cancer Research), will assist Dr. Eric C. Holland and the mentoring team in providing Dr. Jones with the mentorship and resources that she needs to ensure her success. Research: Malignant gliomas account for the vast majority of primary brain tumors, with glioblastoma (GBM) being the most frequent, malignant and deadly overall. Over the past several decades there have been only modest improvements in survival and only a few significant advances in the therapeutic management for GBM. Corticoisteroids such as dexamethasone (Dex) have remained the standard of care for resolving brain tumor-associated neurological symptoms for decades, so prevalent that they can be thought of as part of the disease process itself. However, it remains unclear which cell population(s) and molecular factors are most affected by this therapy. Nor is it clear what effect Dex has on the effectiveness of the standard DNA damaging therapy for GBM such as radiation or alkylating agents. Our data from homogenized tumors and IHC studies from mice treated with Dex show that Dex suppresses the expression of genes and proteins involved in cell proliferation. If Dex decreases cell proliferation of the tumor cells themselves (Olig2+ cells) it is possible that it may decrease the efficacy of anti-neoplastic therapy. This study will provide valuable insight into the mechanism of how Dex works and potentially lead to a paradigm shift in how neurologic symptoms are managed in glioma. We will address the hypothesis that Dex inhibits tumor cell proliferation either in a direct cell autonomous manner or indirectly through microglia; and because of its anti-proliferative effect, it may compromise the effectiveness of standard cytotoxic therapy. We will use a variety of sophisticated genetically engineered mouse models of GBM and leverage in vitro co-culuture models to address the following specific aims: 1) To determine whether Dex inhibits proliferation in the tumor cell population in vivo; 2) To determine the transcriptional effects of Dex on tumor-associated microglial cells and their secreted products; 3) To determine whether Dex antagonizes the anti-tumor effect of standard therapy; and 4) To determine whether compounds targeting microglia function in vivo can lead to a comparable edema reduction as Dex.

描述（由申请人提供）：候选人：Terreia Jones博士是田纳西大学健康科学中心（UTHSC）临床药房的助理教授。她在VA医疗中心（田纳西州孟菲斯）完成了临床药学实践的居住培训，她的研究金培训重点是在圣裘德儿童研究医院（田纳西州孟菲斯）的抗leukemia疗法的药物遗传学。琼斯博士现在正在建立一项研究计划，该研究计划在世界知名的脑癌生物学家和神经外科医生Eric C. Holland博士的指导下进行神经肿瘤学。琼斯博士职业发展的目标集中在她成为成功的临床脑癌科学家的愿望上，其中包括：在神经肿瘤学领域建立强有力的合作，2）出版与脑癌有关的高影响力出版物，以及3）获得校外资金以支持她的研究。她的研究职业发展计划的关键要素包括对纪念斯隆·凯特林癌症中心的延长访问，以在她的导师实验室中获得实验技术；参加并在经常出现的机构研讨会（田纳西大学健康科学中心，圣裘德儿童研究医院和纪念斯隆·凯特林）举行；以及与她的咨询委员会的频繁会议，该委员会由熟悉的脑癌科学家组成，以寻求指导和支持。该奖项的研究将每年在科学会议上进行，预计将在该奖项的任期内至少产生4-8个手稿，并导致成功的R01提交。环境：UTHSC致力于提供必要的基础设施来培养琼斯博士的职业发展，并提供了一个很好的环境，可以在其中进行训练，无论是以非凡的实验室空间和设备的形式进行物理上的训练。 UTHSC和圣裘德校园之间有许多相关的研讨会，可以增强她在癌症生物学方面的知识。她得到了政府的压倒性支持，在部门主席和院长的陪同下，他们在临床药房中拥护竞争科学。到目前为止，该大学的支持是帮助琼斯博士与荷兰博士建立富有成果的关系。正如应用程序中所详细介绍的那样，院长和主席都致力于保护她75％的时间致力于她的职业发展。 Larry Pfeffer博士（UTHSC癌症研究中心的同事兼主任）将协助Eric C. Holland博士和指导团队为Jones博士提供她所需的指导和资源来确保自己的成功。研究：恶性神经胶质瘤占绝大多数原发性脑肿瘤，胶质母细胞瘤（GBM）是最常见的，最恶性和致命的。在过去的几十年中，GBM治疗管理的生存只有适度的改善，并且只有少数重大的进步。数十年来，诸如地塞米松（DEX）之类的皮质司令一直是解决与脑肿瘤相关的神经系统症状的护理标准，因此普遍存在，可以将其视为疾病过程本身的一部分。但是，目前尚不清楚哪些细胞群和分子因素受此疗法影响最大。也不是 清除DEX对GBM的标准DNA损害疗法的有效性（例如辐射或烷基化剂）具有什么作用。我们来自用DEX处理的小鼠均质肿瘤和IHC研究的数据表明，DEX抑制了与细胞增殖有关的基因和蛋白质的表达。如果DEX降低肿瘤细胞本身（Olig2+细胞）的细胞增殖，则可能会降低抗塑性疗法的功效。这项研究会 提供宝贵的洞察力，了解DEX的工作原理，并有可能导致神经瘤症状如何管理神经系统症状的范式转变。我们将解决以下假设：DEX以直接细胞自主的方式或通过小胶质细胞间接抑制肿瘤细胞的增殖。并且由于其抗增殖作用，它可能会损害标准细胞毒性疗法的有效性。我们将使用各种复杂的GBM基因工程小鼠模型并利用体外共塑模型来解决以下特定目的：1）确定DEX是否抑制体内肿瘤细胞群体的增殖； 2）确定DEX对肿瘤相关的小胶质细胞及其分泌产物的转录作用； 3）确定DEX是否拮抗标准治疗的抗肿瘤作用； 4）为了确定靶向小胶质细胞功能的化合物是否会导致可比较的水肿降低与dex。