An Emerging Model of a Hematopoietic Stem Cell Niche in Drosophila

描述(由申请人提供)： 最早分离的体细胞之一是从脊椎动物的骨髓中分离出来的，当 移植成了对许多血液、免疫和代谢遗传疾病的治疗干预。脊椎动物中这些细胞的研究启发了其他组织干细胞的研究。虽然这些细胞上有大量的转录图谱数据，但这些遗传网络在其功能中的作用仍不清楚。我们利用淋巴腺，遗传模式生物黑腹果蝇的造血器官，作为了解体细胞干细胞功能的生物学框架。我们的研究已经确定了淋巴腺中的一个造血干细胞生态位，并证明了这个系统的实用性，因为它概括了脊椎动物骨髓中存在的许多发育原理。我们的目标是描述三龄幼虫淋巴腺干细胞群体中细胞分化的遗传决定因素。我们的第一个特定目标是确定维持果蝇淋巴中造血祖细胞所需的生态位信号的作用。我们已经确定了与生态位的建立和维持有关的信号通路。通过使用分子遗传学方法，我们将剖析那些调节造血祖细胞分化和自我更新能力的信号。我们的第二个特定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。不偏不倚的 基因筛查的目标是识别产生造血干细胞所需的新的基因决定因素。职业发展活动包括遗传学和发育生物学方面的指导和课程。长期的职业目标包括一个学术职位，在那里我可以从事干细胞生物学和再生方面的发育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，更好地了解调控果蝇造血干细胞发育和维持的机制将为探索人类疾病(如白血病)提供新的机制和治疗途径。 (摘要结束)

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)