NF Center: From Animal Models to Therapeutics

NF1肿瘤抑制基因的突变会导致1型神经纤维瘤病(NF1)。NF1编码一个 GTP酶激活蛋白(GAP)为p21ras(RAS)，称为神经纤维素。患有NF1的人有广泛的 各种表现，包括病理性皮肤神经纤维瘤和丛状 神经纤维瘤。对皮肤癌、乳腺癌和胰腺癌的研究强调了 炎性细胞改变微环境，促进恶性生长。同样，利用 基因工程小鼠缺乏NF1(NF1)的小鼠同源物，我们的合作者Dr。 Parada(朱，《科学》杂志，2002)发现肿瘤中NF1单倍体缺失 神经纤维瘤的发生需要微环境。基于这些先前的见解，一个主要的 本申请的重点将是在功能上定义已知的NF1+/-细胞之间的相互作用如何 利用人类和小鼠细胞，微环境促进神经纤维瘤的形成。定义 这些促进肿瘤发生的相互作用的分子和生化性质对于确定 用于临床前试验的药物靶点。我们小组之前提供了第一个遗传学、细胞学和 NF1单倍体不足改变肥大细胞命运的生化证据(Ingram，JEM，2000,2001)。 肥大细胞释放生长因子和其他分子，共同促进血管生成，改变 细胞外基质和细胞生长的关系。我们最初的研究集中在单倍体不足的作用上。 NF1在肥大细胞功能调节中的作用及肥大募集的生化机制 细胞对肿瘤微环境的影响(Yang，JCI 2003)。我们现在建议将这些观察扩展到 研究肥大细胞改变NF1-I-Schwann细胞命运的潜在机制，以及其他 神经纤维瘤微环境中的谱系。我们假设NF1+/-内皮细胞和 成纤维细胞具有固有的功能表型，这些表型会被分泌蛋白进一步干扰。 由NF1+/-肥大细胞释放。我们将通过体外和体内研究来验证这些假说，利用基因 目前用于治疗其他癌症和最先进组织的交叉和药理药物 成像。最后，将在肿瘤微环境的原生人类谱系中进行研究，以 验证小鼠模型是否忠实地概括了人类血统的表型。

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1). NF1 encodes a GTPase activating protein (GAP) for p21ras (Ras) called neurofibromin. Individuals with NF1 have a wide range of manifestations including the pathognomonic cutaneous neurofibromas and plexiform neurofibromas. Studies in cutaneous, mammary, and pancreatic cancers have emphasized the role of inflammatory cells altering the microenvironment and facilitating malignant outgrowth. Similarly, utilizing genetically engineered mice that are deficient in the murine homologue of NF1 (Nf1), our collaborator, Dr. Parada (Zhu, Science, 2002), found that haploinsufficiency of Nf1 in lineages within the tumor microenvironment was required for development of neurofibromas. Based on these prior insights, a major focus of this application will be to functionally define how the interactions between the known Nf1 +/- cells in the microenvironment promote neurofibroma formation utilizing both human and murine cells. Defining the molecular and biochemical nature of these interactions in promoting tumorigenesis is critical for identifying drug targets to be used in preclinical trials. Our group previously provided the first genetic, cellular, and biochemical evidence that haploinsufficiency of Nf1 alters cell fates in mast cells (Ingram, JEM, 2000, 2001). Mast cells release growth factors and other molecules that collectively promote angiogenesis, the alteration of the extracellular matrix and cell growth. Our original studies focused on the role of haploinsufficiency of Nf1 in modulating mast cell functions and the biochemical mechanisms underlying the recruitment of mast cells to the tumor microenvironment (Yang, JCI 2003). We now propose to extend these observations to examine the mechanisms underlying the role of mast cells in altering Nf1 -I- Schwann cell fates, and other lineages within the neurofibroma microenvironment. We hypothesize that Nf1 +/- endothelial cells and fibroblasts have an intrinsic gain of function phenotypes which are further perturbed by secretory proteins released by Nf1 +/- mast cells. We will test these hypotheses with in vitro and in vivo studies, utilizing genetic intercrosses and pharmacologic agents currently used to treat other cancers and state of the art tissue imaging. Finally, studies will be conducted in primary human lineages of the tumor microenvironment to verify that the murine model faithfully recapitulates the phenotypes in human lineages.