Cellular and Molecular Studies of Leukemic Stem Cellss

白血病干细胞的细胞和分子研究

基本信息

批准号：
6999328
负责人：
Craig T. Jordan
金额：
$ 27.38万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-16 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6999328
关键词：
Adenoviridae NOD mouse SCID mouse acute myelogenous leukemia antisense nucleic acid apoptosis gel mobility shift assay human tissue neoplasm /cancer genetics neoplastic growth nuclear factor kappa beta salicylate stem cells transfection /expression vector tumor suppressor proteins western blottings

项目摘要

DESCRIPTION (provided by applicant): The past several years have seen a tremendous expansion in the field of stem cell biology. Numerous advances have occurred in understanding the biological relevance of stem cells, as well as their specific molecular properties. An important part of this new era in stem cell science relates directly to hematologic malignancies. Recent studies have led to the identification of a leukemic stem cell (LSC) population in patients with acute myelogenous leukemia (AML). LSCs are sufficient to perpetuate human leukemic cell growth in long-term culture assays and in the murine NOD/SCID model system. As a consequence of these data, it has been proposed that LSCs are central to the pathogenesis of human myeloid leukemia in vivo. Therefore, the primary objective of this application is to define novel molecular properties of LSCs and to exploit such properties to induce LSC-specific apoptosis. With this goal in mind, our studies have focused on defining unique characteristics of the LSC population. To date, we have shown that primitive AML cells aberrantly regulate several factors related to control of cell death decisions. Further, we have developed a model system in which primary AML cells are induced to undergo apoptosis, but normal cells are spared. Thus, we hypothesize that by targeting specific molecular events it will be possible to preferentially induce apoptosis in the LSC population. This hypothesis will be examined through experiments designed to: 1) characterize the molecular basis of apoptosis in primary AML cells, 2) expand strategies for preferential induction of LSC apoptosis, and 3) use molecular genetic strategies to define critical apoptosis control genes that function in LSCs. Collectively, these efforts will advance our understanding of basic mechanisms that underlie leukemic transformation and will improve strategies for the preferential ablation of LSCs.

描述（由申请人提供）：在过去的几年里，干细胞生物学领域的巨大扩展。取得了许多进展发生在理解干细胞的生物学相关性以及它们特定的分子特性。这个新时代的重要组成部分细胞科学与血液恶性肿瘤直接相关。最近的研究有导致患者体内白血病干细胞（LSC）群体的鉴定患有急性髓性白血病（AML）。 LSC足以让人类永存长期培养测定和小鼠 NOD/SCID 中白血病细胞的生长模型系统。根据这些数据，有人建议 LSC 是人骨髓性白血病体内发病机制的核心。所以，本申请的主要目的是定义新型分子 LSC 的特性，并利用这些特性来诱导 LSC 特异性细胞凋亡。考虑到这一目标，我们的研究重点是定义独特的 LSC 群体的特征。迄今为止，我们已经证明了原始的 AML 细胞异常调节与细胞死亡控制相关的多个因素决定。此外，我们开发了一个模型系统，其中原代 AML 细胞诱导细胞凋亡，但正常细胞幸免。因此，我们假设通过针对特定的分子事件，将有可能优先诱导 LSC 群体凋亡。这个假设将是通过实验进行检查，旨在：1）表征分子基础原代 AML 细胞凋亡的影响，2) 扩大优先策略诱导 LSC 凋亡，3) 使用分子遗传学策略来定义在 LSC 中发挥作用的关键凋亡控制基因。总的来说，这些努力将增进我们对基本机制的理解白血病转化并将改善优惠策略 LSC 的消融。