An Emerging Model of a Hematopoietic Stem Cell Niche in Drosophila

果蝇造血干细胞生态位的新兴模型

• 批准号: 7764775
• 负责人: JULIAN ANTONIO MARTINEZ
• 金额: $ 14.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764775
• 关键词: Animal Model; Basic Science; Biology; Blood Cells; Bone Marrow; Cell Differentiation process; Cell Maintenance; Cell Transplantation; Cell physiology; Cells; Data; Defect; Development; Developmental Biology; Diagnosis; Dominant-Negative Mutation; Drosophila genus; Drosophila melanogaster; Educational process of instructing; Generations; Genetic; Genetic Determinism; Genetic Models; Genetic Screening; Goals; Hematopoietic; Hematopoietic stem cells; Hemocytes; Hereditary Disease; Immune; Immunocompromised Host; Larva; Maintenance; Medical; Mentors; Metabolic; Methods; Modeling; Molecular Genetics; Natural regeneration; Organ; Pathway interactions; Patients; Phosphorus; Population; Positioning Attribute; Process; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Stem cells; Syndrome; System; Techniques; Therapeutic; Therapeutic Intervention; Tissues; Transplantation; Vertebrates; abstracting; career; career development; cell type; design; expectation; graduate student; human disease; leukemia; loss of function; lymph nodes; mutant; notch protein; novel; programs; reconstitution; self-renewal; stem cell biology; stem cell differentiation; stem cell niche

DESCRIPTION (provided by applicant): One of the first somatic stem cells isolated was derived from the vertebrate bone marrow, which when transplanted became a therapeutic intervention for many hematological, immune, and metabolic genetic disorders. The study of these cells in vertebrates has enlightened the study of other tissue stem cells. While a large amount of transcriptional profile data is available on these cells, the role of these genetic networks in their function remains unknown. We utilize the lymph gland, the hematopoietic organ in the genetic model organism Drosophila melanogaster, as a framework for understanding the biology of somatic stem cell function. Our studies have identified a hematopoietic stem cell niche within the lymph gland and demonstrate the utility of this system, as it recapitulates many of the developmental principles present in the vertebrate bone marrow. Our goal is to characterize the genetic determinants of cell differentiation in a population of third instar larva lymph gland stem cells. Our first specific aim is to define the roles of niche signals required for the maintenance of hematopoietic precursors in the Drosophila lymph gland. We have identified signaling pathways involved in the establishment and maintenance of the niche. Through the use of molecular genetic approaches we will dissect those signals that regulate the differentiation and self-renewal capabilities of hematopoietic precursors. Our second specific aim is to determine the cell fate potential of hematopoietic stem cells in the Drosophila lymph gland. We have developed transplantation techniques to characterize the developmental potential of whole lymph glands and dissociated hematopoietic stem cells. An unbiased genetic screen is proposed targeted at identifying novel genetic determinants required for the generation of hematopoietic stem cells. Career development activities include mentoring and coursework in genetics and developmental biology. Long-term career goals include an academic position in which I can pursue basic science research on developmental principles in stem cell biology and regeneration, diagnosis and treatment of patients with genetic syndromes, and teaching of medical and graduate students. Our expectation is that a better understanding of the mechanisms that regulate the development and maintenance of hematopoietic stem cells in Drosophila will provide novel mechanisms and therapeutic pathways to be explored in human disease, such as leukemia. (End of Abstract)

描述（由申请人提供）： 第一批分离的体干细胞之一来源于脊椎动物的骨髓， 移植成为许多血液学、免疫和代谢遗传疾病的治疗干预。这些细胞在脊椎动物中的研究启发了其他组织干细胞的研究。虽然在这些细胞上有大量的转录谱数据，但这些遗传网络在其功能中的作用仍然未知。我们利用淋巴腺，在遗传模式生物果蝇的造血器官，作为一个框架，了解体干细胞功能的生物学。我们的研究已经确定了淋巴腺内的造血干细胞龛，并证明了该系统的实用性，因为它概括了脊椎动物骨髓中存在的许多发育原则。我们的目标是在三龄幼虫淋巴腺干细胞的人口细胞分化的遗传决定因素的特点。我们的第一个具体目标是确定的作用所需的维持造血前体细胞在果蝇淋巴腺的小生境信号。我们已经确定了参与建立和维护的生态位的信号通路。通过使用分子遗传学方法，我们将剖析这些信号，调节造血前体细胞的分化和自我更新能力。我们的第二个具体目标是确定果蝇淋巴腺中造血干细胞的细胞命运潜力。我们已经开发了移植技术来表征整个淋巴腺和分离的造血干细胞的发育潜力。无偏 提出了遗传筛选，其目标是鉴定造血干细胞产生所需的新的遗传决定簇。职业发展活动包括遗传学和发育生物学方面的辅导和课程。长期的职业目标包括一个学术职位，在这个职位上，我可以从事干细胞生物学和再生发展原理的基础科学研究，诊断和治疗遗传综合征患者，以及教授医学和研究生。我们的期望是，更好地了解调节果蝇造血干细胞发育和维持的机制，将为人类疾病（如白血病）提供新的机制和治疗途径。 (End摘要）