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Double Duty: Elucidating the Effects of Estrogen on Tumor Cells and their Microenvironment in Lymphangioleiomyomatosis

双重职责：阐明雌激素对淋巴管平滑肌瘤病中肿瘤细胞及其微环境的影响

基本信息

批准号：
10469668
负责人：
Briaunna Monet Nyika Minor
金额：
$ 4.68万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469668
关键词：
Advisory Committees Affect Age Angiomyolipoma Animals Antiestrogen Therapy Basic Science Biological Assay Biological Models Blood Bone Marrow Cancer Model Cell Line Cell Proliferation Cells Characteristics Chronic Complex Data Development Disinhibition Environment Estradiol Estrogens Ethics FRAP1 gene Fellowship Female Flow Cytometry Future Genes Genetic Models Genomics Goals Growth Health Human In Vitro Infection Inflammation Inflammatory Instruction Knock-out Knockout Mice Knowledge Laboratories Leadership Leiomyoma Lung Lung diseases Lymphangioleiomyomatosis Malignant Neoplasms Mediating Mentorship Metastatic Neoplasm to the Lung Methods Mind Modeling Mus Mutation Myeloid-derived suppressor cells Myometrial Natural Immunity Nature Neoplasm Metastasis Null Lymphocytes Outcome Outcomes Research Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physicians Play Positioning Attribute Process Production Property Rattus Regulation Reporting Research Research Personnel Research Proposals Role SLC12A3 gene Scientist Signal Transduction Smooth Muscle Smooth Muscle Myocytes Source Steroids Structure of parenchyma of lung TSC1 gene TSC1/2 gene TSC2 gene Therapeutic Training Translational Research Trauma Tuberous Sclerosis Tumor Suppressor Proteins Tumor-infiltrating immune cells Uterus Withdrawal Woman Xenograft Model Xenograft procedure adenoma anticancer research cancer cell career career development cell growth design functional loss gene product granulocyte hormonal signals improved in vitro Model in vivo inhibitor insight meetings mouse genetics mouse model myometrium neoplastic cell non-genomic novel novel strategies promoter pulmonary function recruit reproductive role model sexual dimorphism side effect skills treatment strategy tumor tumor growth tumor immunology tumor progression

项目摘要

Project Summary Affecting almost exclusively women, lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by estrogen-sensitive metastatic smooth muscle cell-like adenomas that grow slowly, resulting in cystic lung change and loss of pulmonary function. While mTORC1 disinhibition due to loss of TSC1 or TSC2 mediates the development of this malignancy, estrogen play a key role in promoting LAM tumor growth. The Hammes laboratory created a mouse model for LAM whereby TSC2 was specifically knocked out in the uterus of female mice. These animals developed estrogen-sensitive myometrial tumors that shared most characteristics of LAM tumor cells. Interesting, 50% of animals developed lung metastasis, suggesting that LAM cells may come from the myometrium, thus explaining the sexual dimorphism and estrogen sensitivity of LAM. Importantly, while TSC2-null in-vivo tumors were markedly sensitive to estradiol, TSC2-null cell lines are only mildly estrogen- sensitive, suggesting that estrogen may have actions outside of the TSC2-null cells that promote tumor growth. This research proposal focuses on the potential dual effector function of estradiol in promoting LAM progression. The research strategy is designed to examine estrogen modulation of LAM cells as well as their microenvironment. The proposal concentrates specifically on estrogen actions in granulocytic myeloid-derived suppressor cells, which are markedly elevated in the blood and uteri of uterine-specific TSC2-null mice and play a significant role in promoting tumor progression, likely in an estrogen-dependent fashion. These studies will utilize the novel mouse model, TSC2-null xenografts, in-vitro bone marrow stimulation assays, and other methods to determine mechanisms by which estrogen directly promotes TSC2-null cell growth and indirectly promotes myeloid derived suppressor cell production and actions. This fellowship will provide a path for a highly qualified candidate into a career as a physician scientist. The Hammes laboratory has an extensive background in cancer research, mouse genetics, and steroid signaling. The scope of the lab is continuously expanding as it explores the role of innate immunity in cancer models. In addition, the applicant has assembled an advisory committee comprised of experts in hormone signaling, inflammation, and tumor immunology. Her training plan includes courses in ethics, leadership and professional development, as well as research seminars, national meetings and one-on-one instruction. She has positioned herself optimally to achieve these goals under the mentorship of Dr. Hammes, a role model physician scientist with a long track record of training successful investigators in basic and translational research. The institutional environment at Rochester emphasizes and supports collaborative research and is invested in training future physicians and scientists. The knowledge gained from this fellowship will advance the field of LAM research, propose an estrogen-centered strategy for treatment, and fortify the career development of a young trainee devoted to being a physician scientist.

项目概要淋巴管平滑肌瘤病（LAM）几乎只影响女性，是一种罕见的肺部疾病，其特征是雌激素敏感的转移性平滑肌细胞样腺瘤生长缓慢，导致肺囊性变和肺功能丧失。而由于 TSC1 或 TSC2 缺失而导致的 mTORC1 去抑制介导在这种恶性肿瘤的发展过程中，雌激素在促进LAM肿瘤的生长中发挥着关键作用。哈姆斯实验室创建了 LAM 小鼠模型，其中 TSC2 在雌性子宫中被特异性敲除老鼠。这些动物产生了雌激素敏感的子宫肌瘤，具有 LAM 的大部分特征肿瘤细胞。有趣的是，50%的动物发生了肺转移，这表明LAM细胞可能来自子宫肌层，从而解释了 LAM 的性别二态性和雌激素敏感性。重要的是，虽然 TSC2 缺失的体内肿瘤对雌二醇显着敏感，TSC2 缺失的细胞系仅对雌激素轻度敏感。敏感，表明雌激素可能在 TSC2 缺失细胞之外发挥促进肿瘤生长的作用。本研究计划重点关注雌二醇在促进 LAM 进展方面的潜在双重效应功能。该研究策略旨在检查 LAM 细胞的雌激素调节及其作用微环境。该提案特别关注粒细胞骨髓来源的雌激素作用抑制细胞，在子宫特异性 TSC2 缺失小鼠的血液和子宫中显着升高，并发挥作用在促进肿瘤进展中发挥重要作用，可能以雌激素依赖性方式。这些研究将利用新型小鼠模型、TSC2 缺失异种移植物、体外骨髓刺激试验等确定雌激素直接促进 TSC2 缺失细胞生长和间接促进 TSC2 缺失细胞生长机制的方法促进骨髓源性抑制细胞的产生和作用。该奖学金将为高度成为医师科学家职业的合格候选人。 Hammes实验室拥有广泛的背景癌症研究、小鼠遗传学和类固醇信号传导。实验室的范围不断扩大探讨先天免疫在癌症模型中的作用。此外，申请人还收集了一份咨询意见委员会由激素信号、炎症和肿瘤免疫学专家组成。她的训练计划包括道德、领导力和专业发展课程，以及研究研讨会、国家会议和一对一指导。她已将自己置于最佳位置以实现这些目标 Hammes 博士是一位模范医师科学家，拥有长期成功的培训记录基础研究和转化研究的研究者。罗切斯特的制度环境强调和支持合作研究并投资于培训未来的医生和科学家。知识点从这项奖学金中获得的成果将推动 LAM 研究领域的发展，提出一项以雌激素为中心的策略治疗，并加强致力于成为医师科学家的年轻实习生的职业发展。