POST-TRANSCRIPTIONAL REGULATION OF CELL FATE IN EARLY MAMMALIAN DEVELOPMENT

早期哺乳动物发育中细胞命运的转录后调控

• 批准号: 10191941
• 负责人: CAROLYN O SANGOKOYA
• 金额: $ 14.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10191941
• 关键词: 3' Untranslated Regions; Address; Anatomy; Binding Proteins; Biosensor; Cell Differentiation process; Cell Fate Control; Cell model; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Critical Pathways; Data; Development; Development Plans; Developmental Biology; Embryo; Embryonic Development; Endocytosis; Ensure; Environment; Erythropoiesis; Family; Fibroblast Growth Factor; Five-Year Plans; Future; Goals; Grant; Hepatobiliary; High-Throughput Nucleotide Sequencing; Human Development; Immunoprecipitation; In Vitro; Iron; Iron Regulatory Protein 1; Iron-Regulatory Proteins; Knowledge; Laboratories; Leadership; Learning; Maps; Mediating; Mentored Clinical Scientist Development Award (K08); Mentors; Messenger RNA; Methods; MicroRNAs; Modeling; Molecular; Nucleotides; Operative Surgical Procedures; Organogenesis; Pathologist; Pathology; Pathway interactions; Pattern; Physicians; Play; Post-Transcriptional Regulation; Process; RNA-Binding Proteins; Regulation; Reporter; Research; Resolution; Role; Scientist; Signal Transduction; Site; Statistical Methods; Stem cell pluripotency; Technical Expertise; Testing; Training; Transcript; base; career development; crosslink; embryonic stem cell; functional genomics; gastrointestinal; gastrulation; in vivo; mouse model; multidisciplinary; mutant; neurogenesis; pluripotency; profilin; regenerative therapy; single-cell RNA sequencing; skills; stem; stem cell biology; stem cell differentiation; stem cell fate; stem cell self renewal; stem cells; tool; transcriptome

Post-transcriptional regulation by RNA-binding proteins (RBPs) and microRNAs (miRNAs) orchestrate diverse molecular and cellular mechanisms that pattern early mammalian development from embryonic stem cells (ESCs) through gastrulation and lineage commitment. The RBPs Ago2 (Argonaute-2) and IRP (iron regulatory proteins) respectively coordinate miRNA-mediated regulation and cellular iron regulation, mechanisms essential for the proper execution of early embryonic development. In human development, cellular iron regulation is important for non-hematopoietic tissue development, including neurogenesis and gut development, in addition to erythropoiesis. However, the identities and functional roles of miRNA- and IRP-bound targets in cell fate decisions during early embryonic development are largely unknown. A comprehensive understanding of the dynamic relationships of IRPs, miRNAs, and their functional targets during this critical developmental window is needed and can provide a roadmap for functional rewiring in stem/progenitor cell-based regenerative therapies. The central hypothesis of this proposal is that IRP and miRNAs function cooperatively and dynamically on targets that are important regulators of cell fate transitions during mammalian development. As a molecular biologist and pathologist, my long-term goal is to understand and use these integrated pathways of post-transcriptional control to devise new tools and approaches for functional rewiring in stem/progenitor cell-based regenerative therapies. The objective of this project is to dissect the specific roles of post-transcriptional regulation by miRNAs and IRPs on cell fate decisions in early mammalian development and to build platforms to model cellular iron throughout early mammalian development. This project objective will be achieved by 1) determining the impact of IRP and miR-290-mediated regulation on Profilin-2, a known regulator of ESC differentiation, 2) identifying and functionally dissecting the global network of bound IRP and miRNA targets, and 3) developing biosensor platforms that model cellular iron utilization in vitro and in vivo during early embryonic development. The proposed studies are the core components of the Mentored Clinical Scientist Development Award (K08) for Dr. Carolyn Sangokoya. Dr. Sangokoya is a board-certified Anatomic Pathologist with subspeciality expertise in surgical and gastrointestinal/hepatobiliary pathology. This proposal encompasses a five-year plan to address gaps in specific research and professional skills as she transitions to independence as a physician-scientist. This grant is a training vehicle for Dr. Sangokoya to 1) build knowledge in statistical methods for functional genomics, 2) learn and expand technical skills in generating mouse models, 3) perform single-cell RNA-sequencing studies, and 4) develop professional scientific leadership and lab management skills in transition to leading a successful laboratory. To achieve these goals, Dr. Sangokoya and her multidisciplinary scientific advisory and mentoring team have devised a 5-year career development plan. The proposed training, didactics, and research in the rich research environment at UCSF will ensure a successful and productive transition to independence.

转录后调控由rna结合蛋白（rbp）和microrna （mirna）协调