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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：
10321203
负责人：
Briaunna Monet Nyika Minor
金额：
$ 4.6万
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/10321203
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 protein complex 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/antagonist 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.

项目总结