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MAST CELL DIFFERENTIATION IN VITRO

肥大细胞体外分化

基本信息

批准号：
2607767
负责人：
THOMAS F HUFF
金额：
$ 20.52万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 2000-11-30
项目状态：
已结题

项目摘要

Mast cells are the major effector cells in diseases of immediate hypersensitivity. Understanding how mast cells develop from primitive blood cells may have implication for treatment of certain allergic diseases. Because mast cells may be uniquely related to hematopoietic stem cells, studies of early events in mast cell differentiation may have broader implications for hematopoiesis in general. The research proposed in this grant application extends the mast cell model system developed in the previous grant period. This system takes advantage of the fact that committed progenitors, but not uncommitted ones, can respond to stem cell factor alone by production of mast cell colonies in methylcellulose. There is continuing attention to the different roles that the c-kit/stem cell factor receptor-ligand complex may play in different stages of differentiation may have broader implications for hematopoiesis in general. The research proposed in this grant application extends the mast cell model system developed in the previous grant period. This system takes advantage of the fact that committed progenitors, but not uncommitted ones, can respond to stem cell factor alone by production of mast cell colonies in methylcellulose. There is continuing attention to the different roles that the c-kit/stem cell factor receptor-ligand complex may play in different stages of differentiation; however, the major focus in this grant application addresses Fc receptors on mast cells and their progenitors, because of recent provocative findings that in mast cells, both FcRI and FcRIII associated gamma chain dimers to transduce signals for activation and cytokine biosynthesis. We are particularly interested in the possibility that an induced autocrine IL-3 loop may be critical element in the committed state of these progenitors. The first specific aim is to determine whether bone marrow progenitors, particularly those which may be part of the early mast cell lineage, bear FcRI and FcRIII and if these receptors transduce a signal to induce an autocrine IL-3 loop which is necessary for commitment. In the second specific aim, mast cell-committed progenitors or granulated mast cells from MLN or peritoneal washouts will be tested to determine if FcRI/FcRIII-mediated signalling affects expression of autocrine cytokines, GATA transcription factors, or proteases. We will also determine if the continued occupancy of FcRI on mast cells in necessary for continued division of successive generations of daughter cells. The third specific aims takes advantage of an exciting new models system for the study of hematopoiesis; embryonic stem (ES) cell cultures. Once these very primitive cells are allowed to differentiate in culture, the expression of message and protein for FcRI/FcRIII will be monitored to correlate with the appearance of mast cells and autocrine IL-3 inducibility. These experiments may reveal similarities or differences between proposed in this grant application should contribute not only to our understanding of mast cell differentiation but also to Fc receptor ontogeny and stem cell development.

肥大细胞是即刻疾病的主要效应细胞。过敏症。了解肥大细胞是如何从原始细胞发育而来的血细胞可能对某些过敏症的治疗有意义疾病。因为肥大细胞可能是唯一与造血有关的细胞干细胞，肥大细胞分化早期事件的研究可能已经对一般的造血有更广泛的影响。这项研究建议在此授权应用程序中扩展了所开发的主单元模型系统在前一批款期内。这个系统利用了这样一个事实忠诚的祖先，而不是不忠诚的祖先，可以对干做出反应通过在甲基纤维素中产生肥大细胞集落而单独产生的细胞因子。 C-Kit/STEM的不同作用一直受到关注细胞因子受体-配体复合体可能在不同阶段发挥作用分化可能对造血细胞有更广泛的影响将军。在这项拨款申请中提出的研究延长了在上一次赠款期间开发的肥大单元模型系统。这系统利用了这样一个事实，即忠诚的祖先，但不是未承诺的，可以单独通过产生干细胞因子来反应甲基纤维素中的肥大细胞集落。人们继续关注…… C-kit/干细胞因子受体-配体的不同作用复合体可能在分化的不同阶段发挥作用；然而，这项赠款申请的主要重点是解决桅杆上的Fc受体细胞及其祖细胞，因为最近具有挑衅性的发现在肥大细胞中，FcRI和FcRIII都与伽马链二聚体相关传递激活和细胞因子生物合成的信号。我们是尤其感兴趣的是，诱导自分泌的IL-3 循环可能是这些祖细胞承诺状态中的关键因素。第一个具体目标是确定骨髓祖细胞是否，尤其是那些可能属于早期肥大细胞谱系的熊类 FcRI和FcRIII，如果这些受体传递信号诱导自分泌IL-3环路，这是承诺所必需的。在第二个特定目的，肥大细胞致病的祖细胞或颗粒肥大细胞将对淋巴管或腹膜冲洗液进行检测，以确定是否 FcRI/FcRIII介导的信号转导影响自分泌的表达细胞因子、GATA转录因子或蛋白酶。我们还将确定是否需要继续占用主信元上的FcRI 用于子代细胞的持续分裂。这个第三个特定目标利用了令人兴奋的新车型系统关于造血学的研究；胚胎干细胞培养。一次这些非常原始的细胞在培养中被允许分化， FcRI/FcRIII的信息和蛋白表达将被监测以肥大细胞的出现与自分泌IL-3的关系诱导性。这些实验可能揭示相似之处或不同之处。在这项拨款申请中提出的建议不仅应有助于我们对肥大细胞分化的理解还包括Fc受体个体发育和干细胞发展。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The mast cell-committed progenitor. II. W/Wv mice do not make mast cell-committed progenitors and S1/S1d fibroblasts do not support development of normal mast cell-committed progenitors.

肥大细胞定向祖细胞。

DOI：
发表时间：
1989
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Jarboe,DL;Huff,TF
通讯作者：
Huff,TF

Stem cell factor activates STAT-5 DNA binding in IL-3-derived bone marrow mast cells.

干细胞因子激活 IL-3 衍生的骨髓肥大细胞中 STAT-5 DNA 的结合。

DOI：
发表时间：
1997
期刊：
Experimental hematology
影响因子：
2.6
作者：
Ryan,JJ;Huang,H;McReynolds,LJ;Shelburne,C;Hu-Li,J;Huff,TF;Paul,WE
通讯作者：
Paul,WE

The expression of stem cell factor and its receptor, c-kit in human endometrium and placental tissues during pregnancy.

妊娠期人子宫内膜和胎盘组织中干细胞因子及其受体c-kit的表达

DOI：
10.1210/jcem.81.3.8772609
发表时间：
1996
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Kauma,S;Huff,T;Krystal,G;Ryan,J;Takacs,P;Turner,T
通讯作者：
Turner,T

IL-4 inhibits mouse mast cell Fc epsilonRI expression through a STAT6-dependent mechanism.

IL-4 通过 STAT6 依赖性机制抑制小鼠肥大细胞 Fc epsilonRI 表达。

DOI：
发表时间：
1998
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Ryan,JJ;DeSimone,S;Klisch,G;Shelburne,C;McReynolds,LJ;Han,K;Kovacs,R;Mirmonsef,P;Huff,TF
通讯作者：
Huff,TF

Inhibition of kit expression in P815 mouse mastocytoma cells by a hammerhead ribozyme.

锤头核酶抑制 P815 小鼠肥大细胞瘤细胞中的试剂盒表达。