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Elucidating the role of Ftz-f1 as a mediator of steroid hormone-dependent activity in stem cells and their progeny

阐明 Ftz-f1 作为干细胞及其后代中类固醇激素依赖性活性调节剂的作用

基本信息

批准号：
9021098
负责人：
Elizabeth Tweedie Ables
金额：
$ 43.49万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9021098
关键词：
Address Alleles Anterior Biological Biological Assay Cell Count Cell Cycle Cell Cycle Regulation Cell Differentiation process Cell Maintenance Cell Proliferation Cell Therapy Cell physiology Cells Childhood Clinical Cues Data Detection Disease Drosophila genus Drosophila melanogaster Ecdysone Embryo Environment Equilibrium Experimental Genetics Future Genes Genetic Graafian Follicles Growth and Development function Health Homeostasis Hormonal Hormones Human Individual Insecta Left Location Maintenance Measures Mediating Mediator of activation protein Methods Molecular Natural regeneration Nuclear Nuclear Hormone Receptors Oocytes Oogenesis Orphan Ovarian Ovary Pathway interactions Physiological Physiology Population Sizes Pregnancy Production Property Receptor Signaling Regenerative Medicine Reproduction Role Signal Pathway Signal Transduction Somatic Cell Staging Stem cells Steroids Techniques Technology Testing Tissues cancer therapy cell type competence factor daughter cell ecdysone receptor germline stem cells in vivo insight interest knock-down meetings mutant novel programs regenerative therapy repaired research study response self-renewal stem stem cell fate stem cell population steroid hormone tool transcription factor

项目摘要

PROJECT SUMMARY Recent advances in cell reprogramming have raised considerable interest in the use of stem cells for regenerative therapies to replace damaged or lost cells. Stem cells integrate a variety of intrinsic and extrinsic cues to maintain their fate and proliferative capacity. Importantly, these cues include steroid hormones, which fluctuate during childhood growth and development, pregnancy, and disease, and nuclear hormone receptors, which receive steroid signals to regulate physiological homeostasis. A basic understanding of how stem cells respond to changes in human physiology is therefore a necessary prerequisite to the increased use of stem cells in clinical therapy. Like other nuclear hormone receptor signaling pathways, the insect steroid hormone ecdysone is known to elicit context-dependent cellular responses; however, it is largely unknown how these responses are achieved. The nuclear hormone receptor Ftz-f1 is an ecdysone target, but it is also required for the maximal transcriptional response of other ecdysone targets (namely, E74 and E75) in embryonic and larval tissues. This suggests that Ftz-f1 activity primes some cells to respond to ecdysone by up- regulating a specific transcriptional pathway. Despite the identification of mutant alleles nearly 25 years ago, no studies to date have addressed the function of Ftz-f1 in the ovary. Our studies will test the central hypothesis that Ftz-f1 acts as a competence factor for ecdysone signaling in the ovary. Germline stem cells (GSCs) in the Drosophila melanogaster ovary are well-suited for these studies, due to their easily accessible anatomical location, sensitivity to steroid hormones, and the availability of genetic and experimental techniques. Our studies will not only reveal important new information about the function of ftz-f1 in stem cells and reproduction, but can also serve as a novel paradigm for the study of context-dependent steroid hormone signaling in vivo. In my new independent lab, we will utilize Drosophila genetic mutants and in vivo cell-specific gene knockdown to investigate whether and how ftz-f1 regulates GSCs and their progeny, and test whether ftz-f1 primes specific cells for ecdysone signaling. In Aim 1, we will examine the role of ftz-f1 in the differentiation of GSCs and their progeny. In Aim 2, we will investigate whether ftz-f1 controls the cell cycle in GSCs and their progeny. In Aim 3, we will use genetic interaction experiments to determine whether ftz-f1 functionally interacts with ecdysone signaling. Given the similarity between Drosophila and human steroid hormone signaling, our study will help elucidate how nuclear hormone receptors differentially regulate context-dependent transcriptional pathways in vivo to control stem cell function.

项目总结