The role of Hedgehog and enteric neural crest cell reprogramming in neuroendocrine differentiation

Hedgehog 和肠神经嵴细胞重编程在神经内分泌分化中的作用

基本信息

批准号：
10723031
负责人：
Suzann Duan
金额：
$ 10.64万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723031
关键词：
3-Dimensional Address Arizona Automobile Driving Award Awareness Biology Cell Line Cell Reprogramming Cells Cellular biology Clinic Complex Data Analyses Development Development Plans Diagnosis Dimensions Duodenum Endocrine Enteral Environment Erinaceidae Event Faculty Gastrointestinal Physiology Gene Deletion Genes Glial Fibrillary Acidic Protein Goals Growth Hormones Human Hyperplasia Incidence Inherited Islet Cell Tumor Knowledge MEN1 gene Malignant Neoplasms Mediating Menin Mentored Research Scientist Development Award Mentors Mentorship Methods Modeling Molecular Molecular Biology Mus Mutation Neoplasms Neoplastic Cell Transformation Neural Crest Neural Crest Cell Neuroendocrine Cell Neuroendocrine Tumors Neurosecretory Systems Organoids Pancreas Paraffin Embedding Pathogenesis Pathway interactions Patient-Focused Outcomes Pattern Phenotype Pituitary Gland Population Prevalence Productivity Regulation Reporter Research Research Personnel Research Project Grants Resource Development Role SHH gene Signal Pathway Signal Transduction Stomach Syndrome System Therapeutic Time Tissue Culture Techniques Tissues Training Transgenes Transgenic Mice Transgenic Organisms Tumor Burden Tumor Suppressor Proteins Universities Work Xenograft procedure career career development defined contribution experience gastroenteropancreatic neuroendocrine tumor gastrointestinal genomic data human model improved inhibitor innovation knock-down molecular marker mouse model neural neuroendocrine differentiation neuroendocrine phenotype novel novel therapeutic intervention overexpression personalized approach pharmacologic programs research facility restraint screening single cell analysis skills smoothened signaling pathway specific biomarkers targeted treatment transcriptomic profiling transcriptomics tumor tumor initiation tumorigenic

项目摘要

PROJECT SUMMARY Despite increasing diagnoses, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) remain poorly understood, both in relation to their molecular pathogenesis and cells-of-origin. My recent work using transgenic mice demonstrated, for the first time, the involvement of enteric neural crest-derived cells (ENCCs) in neuroendocrine differentiation and tumor development driven by Men1 gene deletion. Consistent with its role in cell fate patterning, Hedgehog signaling was implicated in neuroendocrine reprogramming of ENCCs. Menin, encoded by the MEN1 gene, has been shown to regulate Hedgehog signaling in mouse models of pancreatic NET development, however reciprocity between menin and Hedgehog has yet to be studied in ENCCs. This proposal aims to address whether loss of menin in ENCCs drives acquisition of the neuroendocrine cell fate with lineage commitment being actively modulated by Hedgehog signaling. My goals are to define the cells-of- origin for MEN1 GEP-NETs and to decipher the role of Hedgehog in driving neuroendocrine cell patterning. I will combine my experience using novel transgenic mouse models and ex vivo tissue culture techniques with state-of-the-art single cell and spatial transcriptome profiling to define the contribution of ENCCs to neuroendocrine differentiation and GEP-NET development. I hypothesize that reciprocal signaling by menin and Hedgehog drives ENCC reprogramming and gives rise to hyperplastic neuroendocrine cells with tumorigenic potential. This Research Plan will determine whether MEN1-associated GEP-NETs originate from reprogrammed ENCC populations (Aim 1) and decipher the role of Hedgehog signaling in neuroendocrine reprogramming of MEN1 GEP-NETs (Aim 2). During the mentored K01 award period, I will work closely with my primary mentor Dr. Juanita Merchant and co-mentor Dr. Megha Padi, distinguished experts in gastrointestinal biology and single cell analysis respectively, to develop the skillset to accomplish my research and career objectives. My Career Development Plan will facilitate my goal of becoming a productive independent investigator by combining rigorous didactic training and formal mentorship under a team of faculty who bring established expertise in cell and molecular biology, gastrointestinal physiology, large genomic data analysis, and 3-D organoid systems. Finally, the breadth of career development resources and extensive shared research facilities at the University of Arizona make it an ideal environment for me to carry out the proposed research project and achieve my career objectives. By leveraging innovative GEP-NET models and cutting-edge sequencing methods, this award will enable me to establish a state-of-the-art research program with the long- term goal of defining the cellular signals that govern enteric neuroendocrine cell fate.

项目概要尽管诊断数量不断增加，但胃肠胰神经内分泌肿瘤（GEP-NET）的治疗效果仍然不佳对其分子发病机制和起源细胞的了解。我最近的工作使用转基因小鼠首次证明肠神经嵴衍生细胞（ENCC）参与 Men1 基因缺失驱动的神经内分泌分化和肿瘤发展。与其角色一致细胞命运模式中，Hedgehog 信号传导与 ENCC 的神经内分泌重编程有关。梅宁，由 MEN1 基因编码，已被证明可以在小鼠胰腺模型中调节 Hedgehog 信号传导 NET 开发，但是 menin 和 Hedgehog 之间的互惠性尚未在 ENCC 中进行研究。这该提案旨在解决 ENCC 中 menin 的丢失是否会导致神经内分泌细胞命运的获得谱系承诺由 Hedgehog 信号主动调节。我的目标是定义细胞- MEN1 GEP-NET 的起源并破译 Hedgehog 在驱动神经内分泌细胞中的作用图案化。我将结合我使用新型转基因小鼠模型和离体组织培养的经验采用最先进的单细胞和空间转录组分析技术来定义 ENCC 的贡献神经内分泌分化和 GEP-NET 开发。我假设相互信号传递 menin 和 Hedgehog 驱动 ENCC 重编程并产生增生性神经内分泌细胞具有致瘤潜力。该研究计划将确定与 MEN1 相关的 GEP-NET 是否起源来自重编程的 ENCC 群体（目标 1）并破译 Hedgehog 信号在神经内分泌中的作用 MEN1 GEP-NET 的重新编程（目标 2）。在指导K01奖期间，我将与我的同事密切合作主要导师Juanita Merchant博士和联合导师Megha Padi博士，胃肠道领域的杰出专家分别是生物学和单细胞分析，以培养完成我的研究和职业生涯的技能目标。我的职业发展计划将促进我成为一名富有成效的独立人士的目标研究者通过将严格的教学培训和正式的指导相结合，在教师团队的指导下，在细胞和分子生物学、胃肠道生理学、大基因组数据分析和 3-D 类器官系统。最后，广泛的职业发展资源和广泛的共享研究亚利桑那大学的设施使其成为我进行拟议研究的理想环境项目并实现我的职业目标。通过利用创新的 GEP-NET 模型和尖端技术测序方法，这个奖项将使我能够建立一个最先进的研究计划，长期定义控制肠神经内分泌细胞命运的细胞信号的术语目标。