NF Center: From Animal Models to Therapeutics

NF 1肿瘤抑制基因突变导致1型神经纤维瘤病（NF 1）。NF 1编码一种 p21 ras（Ras）的GTP酶激活蛋白（GAP）称为神经纤维蛋白。NF 1患者有广泛的 一系列的表现，包括病理性皮肤神经纤维瘤和丛状 神经纤维瘤皮肤癌、乳腺癌和胰腺癌的研究强调了 炎症细胞改变微环境并促进恶性生长。同样，利用 我们的合作者Dr. Parada（Zhu，Science，2002）发现肿瘤内谱系中Nf 1的单倍不足 微环境是神经纤维瘤发生发展所必需的。根据这些先前的见解，一个主要的 本申请的焦点将是功能性地定义已知的Nf 1 +/-细胞之间的相互作用如何在细胞内发生。 微环境利用人和鼠细胞促进神经纤维瘤形成。定义 这些相互作用在促进肿瘤发生中的分子和生物化学性质对于鉴定 用于临床前试验的药物靶点。我们的小组以前提供了第一个遗传，细胞， Nf 1单倍不足改变肥大细胞中细胞命运的生物化学证据（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， 细胞外基质和细胞生长。我们最初的研究集中在单倍不足的作用， NF-1对肥大细胞功能的调节及其募集肥大细胞的生化机制 细胞与肿瘤微环境的相互作用（Yang，JCI 2003）。我们现在建议将这些观察扩展到 研究肥大细胞在改变Nf 1-I-雪旺细胞命运中的作用机制，以及其他 神经纤维瘤微环境中的谱系。我们假设Nf 1 +/-内皮细胞和 成纤维细胞具有功能表型的内在增益， 由Nf 1 +/-肥大细胞释放。我们将通过体外和体内研究来验证这些假设， 目前用于治疗其他癌症的药物和最新技术水平的组织 显像最后，将在肿瘤微环境的主要人类谱系中进行研究， 验证鼠模型忠实地再现了人类谱系中的表型。

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.