Role of Renin Progenitors in Hematopoiesis

肾素祖细胞在造血中的作用

• 批准号: 8764003
• 负责人: Brian Belyea
• 金额: $ 15.11万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764003
• 关键词: Adult; Age; Aorta; Appearance; Automobile Driving; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocyte Subsets; B-Lymphocytes; Birth; Blood Pressure; Bone Marrow; Bone Marrow Cells; Cell Cycle Progression; Cell surface; Cells; Characteristics; Child; Chronic Lymphocytic Leukemia; Data; Development; Development Plans; Developmental Biology; Diagnosis; Electrolytes; Embryo; Embryonic Development; Embryonic and Fetal Development; Event; Evolution; Fellowship; Foundations; Gene Deletion; Gene Expression; Gene Mutation; Genes; Goals; Gonadal structure; Growth; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Human; Immunophenotyping; Kidney; Knowledge; Laboratories; Life; Liquid substance; Liver; Lymphocyte; Lymphoid; Lymphopoiesis; Malignant - descriptor; Malignant Childhood Neoplasm; Mediator of activation protein; Medical; Mentors; Mesonephric structure; Modeling; Molecular Profiling; Mus; Mutation; Organ; Pathogenesis; Patients; Pattern; Population; Populations at Risk; Predisposition; Publications; Regulation; Renal function; Renin; Research; Research Personnel; Role; Scientist; Series; Spleen; Staging; Stem cells; Testing; Time; Yolk Sac; career; career development; cell type; clinically relevant; design; experience; improved; in vivo; leukemia; leukemogenesis; medical schools; mouse model; neoplastic; notch protein; novel; prevent; progenitor; public health relevance; research study; treatment strategy

DESCRIPTION (provided by applicant): The triggering events and cell of origin for leukemia development are usually unknown. We have recently discovered a novel mouse model of B cell leukemia, in which the Notch mediator RBP-J is deleted within renin- expressing cells. We found that the cell of origin for this model is a B lymphocyte progenitor which expresses renin and experiences malignant transformation upon RBP-J deletion. In this project, we propose to further study renin expression during normal and neoplastic hematopoiesis. We hypothesize that renin-expressing hematopoietic cells represent a primitive component of the hematopoietic system with differential transformative capacity and that RBP-J is necessary for appropriate regulation of these cells. Using in vivo lineage tracing, time and cell specific conditional deletin approaches, gene-expression profiling, and immunophenotyping, we propose to further investigate this novel progenitor cell, including its expression patterns during hematopoietic ontogeny, its contribution to differentiation of hematopoietic organs, and its influence on leukemia development. First, we will study the temporal appearance and identity of renin- expressing cells within hematopoietic organs during embryonic and post-natal life. Second, we will delete RBP-J in renin-expressing cells at specific developmental stages to determine when RBP-J becomes critical to normal development of these cells. Third, we will directly compare the malignant potential of B cell subsets by deletion RBP-J in distinct population of B cells using cell-specific deletion. Dr. Belyea's professional goals are to conduct meaningful bench research that will advance the fields of hematopoiesis and leukemogenesis and ultimately improve the cure rate of childhood cancers. He is supported by an experienced and successful mentoring committee that will provide strategic expertise on embryonic development, hematopoiesis, and lymphocyte development. Dr. Belyea has demonstrated commitment to research by pursuing bench research at multiple steps of his career (undergraduate, medical school, fellowship), having a successful (early) publication record, and generating exciting preliminary data. His career development plan is guided by his primary mentor, Dr. Ariel Gomez, an exceptional scientist, experienced advisor, and a leader in developmental biology. This project and his career development plan will provide the foundation for a successful career as an independent investigator and leader in the field of embryonic origins of childhood cancers.

描述（由申请人提供）：通常未知的白血病开发的触发事件和原始细胞。我们最近发现了一种新型B细胞白血病的小鼠模型，其中notch介体RBP-J在肾素表达细胞内被删除。我们发现，该模型的原始细胞是B淋巴细胞祖细胞，它表达肾素并在RBP-J缺失时经历恶性转化。在这个项目中，我们建议在正常和肿瘤造血过程中进一步研究肾素的表达。我们假设表达肾素的造血细胞代表具有差异转化能力的造血系统的原始成分，而RBP-J对于适当调节这些细胞是必需的。我们建议使用体内谱系跟踪，时间和细胞特异性条件缺失方法，基因表达分析和免疫表型，我们建议进一步研究这种新型的祖细胞，包括其在造血性个性化期间的表达模式，对造血性器官的分化有助于造血性器官和对leukemia的影响。首先，我们将研究胚胎和产后寿命期间造血器官中重量表达细胞的时间外观和身份。其次，我们将在特定发育阶段删除表达肾素的细胞中的RBP-J，以确定RBP-J何时对这些细胞的正常发育至关重要。第三，我们将使用细胞特异性缺失在不同的B细胞中的删除RBP-J直接比较B细胞子集的恶性潜力。 Belyea博士的职业目标是进行有意义的板凳研究，以推动造血和白血病的领域，并最终提高儿童癌症的治愈率。他得到了一个经验丰富且成功的指导委员会的支持，该委员会将提供有关胚胎发展，造血和淋巴细胞发展的战略专业知识。 Belyea博士通过在其职业生涯的多个步骤（本科，医学院，奖学金）的多个步骤中进行替补研究表明了对研究的承诺，并获得了成功的（早期）出版记录，并产生了令人兴奋的初步数据。他的职业发展计划由他的主要导师Ariel Gomez博士指导，他是杰出的科学家，经验丰富的顾问，也是发展生物学的领导者。该项目及其职业发展计划将为成功的职业生涯奠定了基础，成为儿童癌症胚胎起源领域的独立研究者和领导者。