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: 8739631
• 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/8739631
• 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; 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; Health; Healthcare; Homing; Hormonal; Hormones; Human; In Vitro; 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; 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; migration; mortality; neglect; novel; overexpression; paracrine; professor; progesterone receptor negative; receptor expression; research study; response; response to injury; skills; steroid hormone; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; young woman

DESCRIPTION (provided by applicant): 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 te 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.

描述（由申请人提供）：候选人是科罗拉多大学安舒茨医学校区（AMC，赞助机构）的博士后研究员，即将转为研究助理教授。她的目标是在一个大学建立并领导一个外部资助的实验室。 大学级别的研究机构，最直接的是在未来三年内过渡到完全独立的地位。她的背景、研究经验和出版物记录证明了她对癌症研究事业的承诺、她进行这些研究的适合性以及她进行创新和高度转化研究的能力。职业发展计划和拟议的研究旨在为候选人提供独立开展研究中枢神经系统转移性疾病激素调节的潜在机制所需的技能、经验和薪资支持。该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，以便在 R01 资金方面具有竞争力。该候选人得到了导师和合作者团队的大力支持，以及机构对她职业发展的坚定承诺。候选人所在的机构是 NCI 指定的癌症中心，拥有优秀的乳腺癌研究小组和设备齐全的设施。研究环境是支持研究计划和候选人职业生涯的最佳环境。研究计划：脑转移是癌症患者的一个重大医疗保健问题。 10% 至 16% 的转移性乳腺癌患者会出现有症状的脑转移，约 80% 的患者会在诊断后一年内死亡。经常转移至大脑的乳腺肿瘤中缺乏雌激素受体（ER）表达，导致人们忽视了激素信号传导在乳腺癌脑转移进展中的作用的研究。原发性和转移性 ER-乳腺癌不采用抗雌激素疗法治疗，因为人们认为抗雌激素疗法无效。然而，初步数据显示，17-β-雌二醇 (E2) 会诱导星形胶质细胞（围绕和浸润脑转移瘤的细胞）上调 EGFR 配体。此外，脑转移细胞系对 E2 处理的星形胶质细胞的反应显示出迁移和增殖增加。由于 EGFR 在脑转移性乳腺肿瘤中过度表达，并且其激活是侵袭、迁移和转移的已知驱动因素，因此推测这是 E2 诱导的旁分泌信号传导促进 ER-乳腺癌脑转移能力的机制之一。性腺或肾上腺产生的类固醇激素可以穿过血脑屏障，也可以由神经元和星形胶质细胞中表达的芳香酶局部产生。重要的是，用于治疗 ER+ 肿瘤的芳香酶抑制剂和抗雌激素可以穿过血脑屏障，并且由于它们对大脑微环境的影响，可用于治疗所有转移性脑肿瘤。该提案将测试新的假设，即雌激素介导的脑微环境反应，特别是由星形胶质细胞介导的反应，有助于独立于肿瘤 ER 状态的转移进展，并且抗雌激素疗法将有效治疗脑转移。目标 1 将检验以下假设：E2 激活星形胶质细胞中基因组 ER 依赖性反应，导致分泌影响脑转移的生长因子。目标 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侵袭、迁移和增殖的机制。目标 3 将检验 E2 导致脑转移的假设 ER-乳腺癌细胞在体内定植。