SELECTIVE APPROACHES TO HEMATOPOIETIC STEM CELL AGONISTS

造血干细胞激动剂的选择性方法

• 批准号: 2718977
• 负责人: Katherine S Bowdish
• 金额: $ 8.75万
• 依托单位: PROLIFARON, LLC
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2718977
• 关键词: antibody; bioassay; chickens; genetic library; hematopoiesis; hematopoietic stem cells; laboratory rabbit; method development; stimulant /agonist

Adult hematopoiesis originates from primitive pluripotent stem cells in the bone marrow. In vitro expansion of hematopoietic stem cells is a major goal of experimental and clinical hematology. In fact, gene therapy of primitive hematopoietic cells has been hindered by the inability to routinely expand stem cells in culture. The objective of this proposal is to develop a new and novel screen that will identify factors that cause bone marrow stem cells to self renew. In phase I, we will construct combinatorial libraries, and identify ligands specific to the surface of primitive human and murine hematopoietic stem cells and murine stem cell lines. Following this, we will design and perform high throughput screens to identify mimetic molecules that behave as agonists in proliferation of hematopoietic stem cell lines. In phase II, individual candidates will be tested in a variety of assays on primary human primitive hematopoietic cells. These assays should distinguish true stem cell renewal from proliferation in conjunction with lineage commitment. PROPOSED COMMERCIAL APPLICATIONS: Agonists identified in phase I will be provided to the medical and research community in the form of reagents for gene therapy to expand stem/progenitor cells in vitro, to improve transduction of hematopoietic stem/progenitor cells by retroviral vectors for sustained therapeutic benefit, to improve blood cell production in vivo for cost-effective therapeutics in myelosuppression and for dose-intensification treatment of various diseases, as reagents for immunodiagnostics, cell separation, and research on fundamental mechanisms in hematopoiesis. The libraries should also be a rich, new, inexpensive source of markers for stem and progenitor cell separation.

成体造血起源于原始多能干细胞 骨髓。造血干细胞的体外扩增是 实验和临床血液学的主要目标。事实上，基因治疗 原始造血细胞的发育受到阻碍 常规地在培养物中扩增干细胞。本提案的目的 是开发一个新颖的屏幕来识别因素 使骨髓干细胞自我更新。在第一阶段，我们将建设 组合文库，并识别特定于表面的配体 原始人和小鼠造血干细胞和小鼠干细胞 线。接下来，我们将设计和执行高通量筛选 识别在增殖中充当激动剂的模拟分子 造血干细胞系。在第二阶段，个人候选人将 可以对人类初级造血细胞进行多种检测 细胞。 这些测定应该区分真正的干细胞更新和 增殖与血统承诺相结合。 拟议的商业应用： 第一阶段确定的激动剂将提供给医疗和 以基因治疗试剂形式扩大研究界 体外干/祖细胞，改善造血转导 通过逆转录病毒载体产生干/祖细胞进行持续治疗 效益，改善体内血细胞生成，具有成本效益 骨髓抑制疗法和剂量强化治疗 各种疾病的检测，作为免疫诊断、细胞分离的试剂， 以及造血基本机制的研究。图书馆 也应该是茎和细胞的丰富的、新的、廉价的标记来源。 祖细胞分离。