Neurofibromatosis type 1 Gene Regulates Myelopoiesis

1 型神经纤维瘤病基因调节骨髓生成

• 批准号: 7617949
• 负责人: David W Clapp
• 金额: $ 32.57万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617949
• 关键词: Affect; Apoptosis; Arts; Biochemical; Biochemical Pathway; Bone Marrow Transplantation; Cell physiology; Cells; Complex; Cutaneous; Data; Development; Endothelial Cells; Engineering; F-Actin; Family member; Fibroblasts; Funding; GTPase-Activating Proteins; Genetic; Genetically Engineered Mouse; Hematopoietic; Hereditary Disease; Image; In Vitro; Individual; Inflammatory; Kinetics; Knockout Mice; Life; Link; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary gland; Mediating; Microtubules; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Mutation; Myelopoiesis; NF1 gene; Neurofibromatoses; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Non-Malignant; Pathologic; Patients; Plexiform Neurofibroma; Predisposition; Process; Protein-Serine-Threonine Kinases; Proteins; Ras Signaling Pathway; Recruitment Activity; Research Personnel; Role; Schwann Cells; Signal Pathway; Signal Transduction; Source; Stem Cell Factor; Testing; Tumor Suppressor Genes; abstracting; in vivo; insight; man; mast cell; migration; mortality; neurofibroma; p21-activated kinase 1; prevent; small molecule; tumor; tumor progression

DESCRIPTION (provided by applicant): Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), the most common genetic disorder in man with a predisposition to cancer. NF1 encodes a GTPase activating protein (GAP) for p21ras (Ras) called neurofibromin, and studies by us and others have shown that the Ras signaling pathways are hyperactive in cells from NF1 patients. Individuals with NF1 have a wide range of malignant and nonmalignant manifestations, including the debilitating plexiform neurofibromas that collectively affect 15-40% of NF1 patients and are a major source of life long morbidity and mortality. Neurofibromas are complex tumors composed of Schwann cells, endothelial cells, fibroblasts, and high concentrations of degranulating mast cells. Studies in cutaneous, mammary, and pancreatic cancers have emphasized the role of inflammatory cells, including mast cells, in altering the tumor microenvironment and facilitating malignant outgrowth. Our group provided the first genetic, cellular, and biochemical evidence that haploinsufficiency of Nf1 alters Ras activity and cell fates in mast cells1, 2. We recently found that Nf1-/- Schwann cells secrete excessive quantities of kit- ligand to recruit mast cells to the tumor microenvironment. 3. Further, using a genetically engineered murine model that closely recapitulates the development of plexiform neurofibromas in NF1 patients, we have now used bone marrow transplantation to demonstrate as a proof of concept that haploinsufficiency of Nf1 in the hematopoietic component of the tumor microenvironment and particularly mast cells is necessary for tumor progression. In this application, we propose to build on these observations and pursue a molecular target identified in the previous funding period. We have recently shown that p21 activated kinase 1 (Pak 1), a serine/threonine kinase, is hyperactivated in Nf1 mast cells2. We hypothesize that Pak1 functions as a key intracellular signaling pathway node that regulates multiple pathologic mast cell processes. Preliminary data from our lab using a Pak1-/- mouse support this hypothesis. Here, we propose to use a genetic intercross to test the role of Pak1 on pathological Nf1 mast cell functions and the biochemical effectors that mediate these functions in vitro. In addition, utilizing the genetically engineered murine model of plexiform neurofibromas and state-of the art experimental imaging developed by investigators on this application, studies to test the role of Pak1 in promoting hematopoietic cell mediated initiation of plexiform neurofibromas in vivo are proposed. Project Narrative: We have previously identified a role for inflammatory mast cells in the genesis of a common type of congenital tumor called plexiform neurofibromas. Studies in this application propose studies in genetically engineered mice to test the role of a protein called Pak1 that we hypothesize are integral to mast cell function and tumor progression. If the hypothesis is correct, we would predict that developing small molecules that inhibit Pak1 function could be useful as a molecular therapy for treatment of plexiform neurofibromas.

描述（申请人提供）：NF1肿瘤抑制基因中的突变引起神经纤维瘤病1型（NF1），这是男性中最常见的遗传疾病，患有癌症。 NF1编码称为Neurofiromin的P21RA（RAS）的GTPase激活蛋白（GAP），我们和其他人的研究表明，NF1患者的细胞中RAS信号通路是多活跃的。 NF1患者具有广泛的恶性和非恶性表现，包括使人衰弱的神经纤维瘤共同影响15-40％的NF1患者，并且是长期发病率和死亡率的主要来源。神经纤维瘤是由雪旺细胞，内皮细胞，成纤维细胞和高浓度脱粒肥大细胞组成的复杂肿瘤。 在皮肤，乳腺和胰腺癌中的研究强调了包括肥大细胞在内的炎症细胞在改变肿瘤微环境和促进恶性产物中的作用。我们的小组提供了第一个遗传，细胞和生化证据，即NF1的单倍不足会改变肥大细胞中的RAS活性和细胞命运1，2。我们最近发现，NF1 - / - Schwann细胞分泌过多的动物量，以使肥大细胞募集肥大细胞至肿瘤微环境。 3。此外，使用基因设计的鼠模型，该模型紧密概述了NF1患者中丛状神经纤维瘤的发展，我们现在已经使用骨髓移植作为概念证明，表明NF1在肿瘤微环境中尤其是MAST细胞的造血成分的NF1的单倍不足，以使其尤其是MAST细胞的必要条件。在本应用程序中，我们建议以这些观察结果为基础，并追求在上一流的资金期间确定的分子靶标。 我们最近表明，在NF1肥大细胞中，P21激活的激酶1（PAK 1）是一种丝氨酸/苏氨酸激酶。我们假设PAK1是调节多种病理肥大细胞过程的关键细胞内信号通路节点。使用PAK1 - / - 小鼠从实验室获得的初步数据支持此假设。在这里，我们建议使用遗传间ro可测试PAK1对病理NF1肥大细胞功能的作用以及在体外介导这些功能的生化效应子。此外，提出了利用研究人员对这项应用的基因设计的丛生神经纤维瘤的鼠模型和先进的实验成像，从而测试了PAK1在促进造血细胞介导的体内造血细胞介导的造血细胞介导的启动中的作用。 项目叙述：我们以前已经确定了炎性肥大细胞在一种称为丛状神经纤维瘤的常见类型的先天性肿瘤的起源中的作用。该应用中的研究提出了对基因工程小鼠的研究，以测试我们假设的称为PAK1的蛋白质的作用，该蛋白质是肥大细胞功能和肿瘤进展不可或缺的。如果假设正确，我们将预测，抑制PAK1功能的小分子可以作为治疗丛状神经纤维瘤的分子治疗。