Hormonal regulation of the brain microenvironment and its contribution to brain m

脑微环境的激素调节及其对脑功能的贡献

• 批准号: 8616552
• 负责人: Diana M. Cittelly
• 金额: $ 14.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-29 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616552
• 关键词: Address; Adrenal Glands; Adverse effects; Affect; Aromatase; Aromatase Inhibitors; Astrocytes; Biology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breast; Breast Cancer Cell; Breast Carcinoma; Breast Diseases; Cancer Patient; Cell Line; Cell Proliferation; Cells; Coculture Techniques; Colorado; Critiques; Data; Development Plans; Diagnosis; Disease; Disseminated Malignant Neoplasm; EGF gene; ERBB2 gene; Environment; Epidermal Growth Factor Receptor; Estradiol; Estrogen Antagonists; Estrogen Receptor Status; Estrogen Receptors; Estrogen Therapy; Estrogen receptor negative; Estrogens; Funding; Genetic Transcription; Genomics; Goals; Gonadal structure; Growth; Growth Factor; Growth Factor Receptors; Healthcare; Homing; Hormonal; Hormones; Human; In Vitro; Individual; Institution; Laboratories; Ligands; MMP9 gene; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Medical; Mentors; Metastatic malignant neoplasm to brain; Microglia; Mus; NCI-Designated Cancer Center; Neoplasm Metastasis; Neurons; Outcome; Paracrine Communication; Patients; Pharmaceutical Preparations; Placebos; Play; Positioning Attribute; Postdoctoral Fellow; Protein Isoforms; Publications; Quality of life; Research; Role; S100 Calcium Binding Protein; Seeds; Signal Transduction; Testing; Therapeutic Intervention; Translational Research; Tumor Suppressor Proteins; Universities; Up-Regulation; Wages; Woman; Writing; anticancer research; autocrine; cancer cell; career; career development; cell motility; chemotherapeutic agent; clinically significant; density; design; experience; hormone regulation; improved; in vivo; innovation; malignant breast neoplasm; meetings; migration; mortality; neglect; novel; overexpression; paracrine; professor; progesterone receptor negative; public health relevance; receptor expression; research study; response; response to injury; skills; steroid hormone; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; young woman

7. Project Summary/Abstract Candidate, Career Development Plan and Environment: The Candidate is a postdoctoral fellow transitioning to Assistant professor of Research at University of Colorado Anschutz Medical Campus (AMC, sponsoring institution). Her goal is to establish and direct an extramurally funded laboratory at a University level research institution and most immediately, to transition to a fully independent position in the next 3 years. Her background, research experience and record of publications demonstrate her commitment to a career in cancer research, her suitability to conduct these studies, and her ability to conduct innovative and highly translational research. The career development plan and proposed studies were designed to provide the candidate with the skills, experiences and salary support necessary to independently perform research studies examining the underlying mechanisms of hormonal regulation of metastatic disease in the CNS. This plan will consolidate the candidate's expertise and produce high impact publications and preliminary data to be competitive for R01 funding. The candidate counts with strong support from her mentors and team of collaborators, as well as strong institutional commitment to her career development. The candidate's institution is a NCI-designated Cancer Center with an outstanding breast cancer research group and exceptionally equipped facilities. The research environment is optimal to support both the research plan and the candidate's career. Research plan: Brain metastases represent a substantial health care problem in cancer patients. Ten to 16% of patients with metastatic breast cancer develop symptomatic brain metastases and ~80% die within one year of diagnosis. The absence of estrogen receptor (ER) expression in breast tumors that frequently metastasize to the brain has led to the neglect of studies on the role of hormone signaling in the progression of breast cancer brain metastasis. Primary and metastatic ER- breast cancers are not treated with anti-estrogen therapies since it assumed they are ineffective. However, preliminary data shows that 17-¿-estradiol (E2) induces upregulation of EGFR ligands by astrocytes, cells that surround and infiltrate brain metastasis. Furthermore, brain metastatic cell lines show increased migration and proliferation in response to E2-treated astrocytes. Since EGFR is overexpressed in brain metastatic breast tumors and its activation is a known driver of invasion, migration and metastasis, it is hypothesized this is one of the mechanisms by which E2-induced paracrine signaling contributes to the brain metastatic ability of ER- breast cancers. Steroid hormones produced by gonads or adrenals cross the blood brain barrier, and are also produced locally by aromatase expressed in neurons and astrocytes. Importantly, aromatase inhibitors and anti-estrogens used for the treatment of ER+ tumors can cross the blood brain barrier and could be useful for treatment of all metastatic brain tumors because of their effects on the brain microenvironment. This proposal will test the novel hypothesis that estrogen-mediated responses of the brain microenvironment, particularly mediated by astrocytes, contributes to metastases progression independently of tumor ER status, and that anti-estrogen therapies will effectively treat brain metastases. Aim 1 will test the hypothesis that E2 activates genomic ER- dependent responses in astrocytes, leading to the secretion of growth factors that affect brain metastases. Aim 2 will elucidate the mechanism(s) by which estrogen-stimulated astrocytes increase brain-metastatic breast cancer invasion, migration and proliferation. Aim 3 will test the hypothesis that E2 contributes to brain metastatic colonization by ER- breast cancer cells in vivo. !

7.项目总结/摘要 候选人，职业发展计划和环境：候选人是一名博士后研究员， 科罗拉多大学安舒茨医学院研究助理教授（AMC，赞助 机构）。她的目标是建立和指导一个在大学水平的研究校外资助的实验室 机构，并立即过渡到一个完全独立的立场，在未来3年。她 她的背景、研究经验和出版记录表明她致力于从事 癌症研究，她是否适合进行这些研究，以及她进行创新和高度评价的能力。 翻译研究职业发展计划和拟议的研究旨在提供 具有独立进行研究所需的技能、经验和工资支持的候选人 研究中枢神经系统转移性疾病激素调节的潜在机制。这个计划将 巩固候选人的专业知识，并产生高影响力的出版物和初步数据， R 01融资的竞争。候选人在导师和团队的大力支持下， 合作者，以及对她的职业发展的强有力的机构承诺。候选人所在机构 是一个NCI指定的癌症中心，拥有杰出的乳腺癌研究小组， 设施齐全。研究环境是最佳的，以支持研究计划和候选人的 事业 研究计划：脑转移是癌症患者的一个重大医疗问题。10%到16% 的转移性乳腺癌患者出现症状性脑转移，约80%在一年内死亡 诊断。乳腺肿瘤中雌激素受体（ER）表达的缺失， 对大脑的研究导致了对激素信号在乳腺癌进展中作用的研究被忽视。 癌症脑转移原发性和转移性ER-乳腺癌不接受抗雌激素治疗 治疗，因为它认为他们是无效的。然而，初步数据显示，17-<$-雌二醇（E2） 通过星形胶质细胞诱导EGFR配体的上调，星形胶质细胞是围绕和浸润脑转移的细胞。 此外，脑转移瘤细胞系显示响应于E2处理的增强的迁移和增殖。 星形胶质细胞由于EGFR在脑转移性乳腺肿瘤中过表达，其激活是已知的驱动因素， 在侵袭、迁移和转移的过程中，假设这是E2诱导肿瘤细胞增殖的机制之一。 旁分泌信号传导有助于ER-乳腺癌的脑转移能力。类固醇激素 由性腺或肾上腺产生，穿过血脑屏障，也由芳香酶局部产生 在神经元和星形胶质细胞中表达。重要的是，芳香酶抑制剂和抗雌激素用于 ER+肿瘤的治疗可以穿过血脑屏障，并可用于治疗所有转移性肿瘤。 因为它们对大脑微环境的影响。这个提议将考验小说 假设雌激素介导的脑微环境的反应，特别是由 星形胶质细胞，独立于肿瘤ER状态促进转移进展，并且抗雌激素 治疗将有效地治疗脑转移。目的1将检验E2激活基因组ER的假设- 星形胶质细胞中的依赖性反应，导致影响脑转移的生长因子的分泌。目的 2将阐明雌激素刺激的星形胶质细胞增加脑转移性乳腺癌的机制。 癌细胞的侵袭、迁移和增殖。目的3将检验E2对大脑功能的影响这一假设。 ER-体内乳腺癌细胞的转移性定植。 !