A Mouse Model for Human Gastrointestinal Stromal Tumor

描述(由申请人提供)：这项建议的总体目标是通过使用我们最近为这种疾病开发的小鼠模型来研究：1)导致胃肠道间质瘤(GIST)形成的机制和2)治疗干预的后果。 小鼠W基因座编码的Kit受体酪氨酸激酶。KIT功能突变的丧失导致胚胎发生和出生后动物的几个主要细胞系统的主要缺陷，包括配子发生、造血、黑素生成和胃肠道中的卡哈尔间质细胞(ICC)。Kit受体介导的正常功能包括细胞增殖、细胞存活、细胞黏附、细胞迁移、分泌反应和分化。此外，在人类肿瘤中，Kit的致癌激活被认为在胃肠间质瘤(GIST)、肥大细胞增多症/肥大细胞白血病、急性髓系白血病和生殖细胞肿瘤中起作用。在所有这些肿瘤中都发现了激活Kit突变。在发现家族性GIST综合征病例的基础上，我们利用敲入策略，通过Kit受体酪氨酸激酶基因的靶向突变，建立了家族性GIST综合征小鼠模型。我们现在建议使用这个小鼠模型来研究GIST的发生机制，研究治疗干预对GIST小鼠的影响，并阐明肿瘤基因激活的Kit受体的信号机制。此外，我们还建议研究KitV558del突变在胚胎发育过程中对ICC网络发育以及对胚胎心脏发育的影响。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate: 1) mechanisms leading to the formation of gastrointestinal stromal tumor (GIST) and 2) the consequences of therapeutic intervention, by using a mouse model we have recently developed for this disease. The Kit receptor tyrosine kinase encoded at the murine W locus. Kit loss of function mutations result in major deficiencies in several major cell systems during embryogenesis and in the postnatal animal including gametogenesis, hematopoiesis, melanogenesis, and interstitial cells of Cajal (ICC) in the gastrointestinal tract. Normal Kit receptor mediated functions include cell proliferation, cell survival, cell adhesion, cell migration, secretory responses, and differentiation. In addition, in human neoplasia oncogenic activation of Kit is thought to have roles in gastro intestinal stromal tumors (GIST), mastocytosis/mast cell leukemia, acute myelogenous leukemia, and germ cell tumors. Activating Kit mutations are found in all of these neoplasms. Based on the finding of familial cases of GIST syndrome we have developed a mouse model for familial GIST syndrome by targeted mutation of the Kit receptor tyrosine kinase gene using a knock-in strategy. We now propose to use this mouse model to investigate mechanism of the development of GIST, to study the consequences of therapeutic intervention in mice with GIST and to elucidate mechanisms of signaling by oncogenetically activated Kit receptors. We furthermore propose to investigate the effect of the KitV558del mutation on the development of ICC networks during embryonic development and on embryonic heart development.