Integrative mouse pathobiology: GI epithelial biology and genetics

综合小鼠病理学：胃肠道上皮生物学和遗传学

基本信息

批准号：
8226085
负责人：
Hiroshi Nakagawa
金额：
$ 8.67万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-03 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8226085
关键词：
Advisory Committees Affect Benign Biology Carcinoma in Situ Cell Culture Techniques Cell Fate Control Cell Line Cells Characteristics Complex Coupled Cues Cyclin D1 Data Development Disease Disease Progression Dominant-Negative Mutation Dysplasia Epithelial Epithelial Cells Esophageal Esophageal Diseases Esophageal Squamous Cell Carcinoma Esophagus Future Genetic Genetically Engineered Mouse Goals Growth Heterogeneity Histocompatibility Testing Homeostasis Human Human Papillomavirus Image Intervention Keratin Knockout Mice Knowledge Laboratories Lead Life Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of esophagus Mediating Mentors Mesenchymal Mission Modeling Molecular Morphology Mus Mutation NOTCH1 gene Nature Oncogene Proteins Outcome Pathogenesis Pathway interactions Prevention Primary Neoplasm Public Health Regulation Research Resistance Role Shapes Signal Transduction Skin Squamous Differentiation Squamous cell carcinoma Staging Stem cells System Testing Time Tissues Training Transforming Growth Factors Transgenic Mice Transgenic Organisms Transplantation Tumor Biology Tumor Suppressor Proteins base cancer stem cell carcinogenesis epithelial to mesenchymal transition experience gain of function human disease imaging modality in vivo innovation insight keratinocyte loss of function molecular imaging mouse model neoplastic cell notch protein novel novel strategies prevent research study response senescence trait transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Little is known about the role of Notch signaling in esophageal squamous epithelial biology and diseases. In particular, there is a fundamental gap in understanding how Notch signaling contribute to normal esophageal epithelial squamous differentiation, carcinogenesis, and intratumoral cell heterogeneity, characterized by co- existing well-differentiated cell nests (i.e. keratin pearl) and disseminated, invasive poorly differentiated cells with mesenchymal traits found in esophageal squamous cell carcinoma (ESCC), one of the most deadly cancers. Continued existence of this gap represents an important problem because, until it is filled, mechanisms for Notch-mediated esophageal epithelial cell fate regulation will remain largely incomprehensible. The long-term goal is to better understand the molecular mechanisms by which tissue microenvironment influences malignant transformation of esophageal squamous epithelial cells. The objective in this proposal is to define the roles of Notch signaling in normal biology and tumor biology of the esophagus using innovative genetically engineered mouse models. The central hypothesis is that Notch induces squamous differentiation and senescence in a CSL-dependent manner. During tumor progression, microenvironmental cues activate a CSL-independent pathway to enrich migratory cancer stem cells (CSCs). This hypothesis has been formulated on the basis of preliminary data produced in the applicants' laboratories. The rationale for the proposed research is that, once it is known how Notch control cell fates, they can be manipulated pharmacologically, resulting in novel and innovative approaches in the prevention and treatment of ESCC. Guided by strong preliminary data, this hypothesis will be tested by pursuing three interrelated Specific Aims: (1) To elucidate how Notch activities contribute to the early stages of esophageal carcinogenesis in new mouse models; (2) To determine the roles of Notch for tumor progression in a conditional p120-catenin knockout mouse model; and (3) To delineate the roles of Notch in mouse CSCs in a novel orthotopic transplantation model where the tumor microenvironment is recapitulated. Genetic gain-of-function and loss-of-function experiments will be done in an inducible fashion in new mouse models. In vivo live imaging will be performed to assess the Notch-regulated CSC activities in vivo. The proposed research is significant, because it is expected to vertically advance and expand understanding of mechanisms by which esophageal epithelial homeostasis is regulated and in turn, deregulated in esophageal diseases, both benign and malignant, and potentially other squamous diseases in other tissue types, all through an appreciation of mouse pathobiology. Such knowledge will lead to development of innovative pharmacological strategies that will manipulate Notch signaling to alter esophageal cell fates and have the potential to advance in the therapy of ESCC and prevention of disease progression. PUBLIC HEALTH RELEVANCE (provided by applicant): The proposed research is relevant to public health because detailed understanding of the regulatory mechanisms of esophageal squamous differentiation and esophageal cancer stem cells by Notch will fundamentally advance the fields of Notch signaling and esophageal epithelial biology and tumor biology, and provide a platform for new avenues of translational biologically based applications for therapy of esophageal squamous cell carcinoma. Thus, proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human diseases through the power of mouse pathobiology.

描述（由申请人提供）：关于Notch信号在食管鳞状上皮生物学和疾病中的作用知之甚少。特别是，了解缺口信号如何有助于正常的食管上皮鳞状分化，癌变和肿瘤内细胞异质性，其特征是共同分化的细胞巢（即角蛋白珍珠）和侵入性腐烂的细胞，并构成了细胞的细胞，这些细胞构成了细胞的细胞，并构成了细胞的细胞，这些细胞构成了细胞的细胞，这些细胞构成了细胞的特征。（ESCC），最致命的癌症之一。持续存在此差距代表了一个重要的问题，因为在填充后，凹槽介导的食管上皮细胞命运调节的机制将在很大程度上无法理解。长期目标是更好地了解组织微环境影响食管鳞状上皮细胞的恶性转化的分子机制。该提案的目的是使用创新的基因工程小鼠模型来定义Notch信号传导在正常生物学和食管肿瘤生物学中的作用。中心假设是Notch以CSL依赖性方式诱导鳞状分化和衰老。在肿瘤进展过程中，微环境线索激活了与CSL独立的途径富集迁移癌干细胞（CSC）。该假设是根据申请人实验室产生的初步数据提出的。拟议的研究的理由是，一旦知道Notch控制细胞的命运，它们就可以通过药理操纵，从而在预防和治疗ESCC的预防和治疗方面采用新颖和创新的方法。在强有力的初步数据的指导下，将通过追求三个相互关联的特定目的来检验该假设：（1）阐明Notch活动如何在新小鼠模型中促进食管致癌的早期阶段；（2）确定条件P120-Catenin敲除小鼠模型中Notch在肿瘤进展中的作用；（3）在新型的原位移植模型中描绘了小鼠CSC中缺口的作用，其中概括了肿瘤微环境。遗传功能获得和功能丧失实验将在新的小鼠模型中以诱导方式进行。将进行体内实时成像，以评估体内缺口调节的CSC活动。拟议的研究很重要，因为它有望在垂直方面提高和扩展对食管上皮上皮体内稳态的理解，然后通过对其他组织类型的其他组织类型中的其他鳞状疾病进行了良性和恶性疾病，在食管食道疾病中受到了管辖。这种知识将导致创新的药理学策略的发展，这些策略将操纵Notch信号以改变食管细胞的命运，并有可能进步ESCC治疗和预防疾病进展。公共卫生相关性（由申请人提供）：拟议的研究与公共卫生有关，因为对食管鳞状分化的调节机制的详细理解和食管癌干细胞的调节机制从根本上讲将在根本上推进Notch信号传导和食管生物学生物学和肿瘤生物学应用程序的现场，并为新的疾病的应用程序提供了新的疾病，并提供了新的疾病范围的疾病，并为疾病的新型应用程序提供了平台的平台。癌。因此，拟议的研究与NIH使命的一部分有关，即发展基本知识，这将有助于通过小鼠病理生物学的力量来减轻人类疾病的负担。