p21-Activated Kinases as New Therapeutic Targets in Neurofibromatosis Type 1

p21 激活激酶作为 1 型神经纤维瘤病的新治疗靶点

• 批准号: 8094300
• 负责人: JONATHAN CHERNOFF
• 金额: $ 39.51万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094300
• 关键词: Actins; Affect; Animals; Attention; Biochemical; Biological; Bone Marrow; Bone Marrow Cells; Cell Shape; Cells; Chemicals; Coupled; Cytoskeleton; Diffuse; Disease; Disease Progression; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Event; Functional disorder; GTPase-Activating Proteins; Genes; Genetic; Genetic Models; Germ-Line Mutation; Growth; Guanine Nucleotides; Hereditary Disease; Human; In Vitro; Incidence; Inherited; Knockout Mice; Lesion; Link; MAPK14 gene; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Mediating; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; NF1 gene; Neurofibromatosis 1; Pathogenesis; Pathology; Pathway interactions; Patients; Phosphotransferases; Play; Plexiform Neurofibroma; Positioning Attribute; Proteins; Ras Signaling Pathway; Regulation; Role; Schwann Cells; Signal Pathway; Signal Transduction; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Transplantation; base; cell motility; cell type; disease-causing mutation; effective therapy; in vivo; inhibitor/antagonist; mast cell; mitogen-activated protein kinase p38; mouse model; neurofibroma; new therapeutic target; p21 activated kinase; prevent; prototype; public health relevance; small molecule; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Neurofibromatosis type 1 (NF1) is a relatively common inherited disease syndrome caused by germline mutations in the NF1 gene. About one third of NF1 patients develop diffuse, plexiform neurofibromas that can transform to a malignant peripheral nerve sheath tumor - a cancer that is frequently fatal. Remarkably, in human tumors and in mouse models of NF1, neurofibromas almost invariably contain Nf1-null Schwann cells and Nf1 heterozygous mast cells. Transplanting such NF1-prone mice with wild- type bone marrow prevents tumorigenesis, implying that bone marrow derived cells such as mast cells are a required component in pathogenesis, and that targeting signaling pathways in either Schwann cells or mast cells might be of therapeutic benefit. The NF1 gene encodes a large protein with GTPase Activating Protein (GAP) activity towards Ras. Complete or hemizygous loss of the NF1 gene leads to increased Ras activity in both Schwann cells and mast cells, with concomitant activation of downstream effectors that promote proliferation and changes in cell shape and movement. Recently, we have shown that p21-activated kinases play an important role in activating an Erk-mediated proliferation and a p38- mediated motility pathway downstream of Ras in Nf1-deficient mast cells. We postulate that loss of Pak function will diminish activation of key Ras effector pathways in Nf1-deficient Schwann cells as well, and thus could benefit patients with NF1. We propose three aims: 1) We will identify the key substrates of group A Paks in mast cells that affect cell motility; 2) Using pharmacologic and genetic means to disable Paks in Schwann cells derived from Nf1-deficient mice, we will determine if loss of Pak function reverses the activation of MAPK and cytoskeletal alterations in vitro; and 3) We will cross Krox20-cre/Nf1flox/- mice, which develop malignant peripheral nerve sheath tumors, with Pak1 knock out mice, or transplant such NF1 mice with Pak1-/- bone marrow cells, to determine if loss of Pak1, globally or in bone marrow derived cells, affects disease progression. The proposed studies will not only increase our understanding of cardinal cancer-relevant signaling pathways, but could establish the Paks as suitable targets for therapeutic intervention in this otherwise untreatable disease. PUBLIC HEALTH RELEVANCE: p21-activated kinases (Paks) are key regulators of signaling downstream of Ras, a protein that is activated as a result of loss of the NF1 gene. Currently, there are no effective therapies for NF1-related malignancies. We have developed genetic models for studying Pak function in animals, as well as the first specific chemical inhibitor of these enzymes; for these reasons, we are in a unique position to explore the biological role of Paks in NF1 and to determine if these enzymes represent suitable targets for therapy.

描述（由申请人提供）：1型神经纤维瘤病（NF1）是一种相对常见的遗传性疾病综合征，由NF1基因的种系突变引起。大约三分之一的NF1患者发展为弥漫性丛状神经纤维瘤，可转变为恶性周围神经鞘肿瘤，这种癌症通常是致命的。值得注意的是，在人类肿瘤和小鼠NF1模型中，神经纤维瘤几乎无一例外地含有NF1缺失的雪旺细胞和NF1杂合肥大细胞。用野生型骨髓移植这种nf1易感小鼠可以防止肿瘤发生，这意味着骨髓来源的细胞如肥大细胞是发病机制中必需的组成部分，靶向雪旺细胞或肥大细胞的信号通路可能具有治疗益处。NF1基因编码一个对Ras具有GTPase激活蛋白（GAP）活性的大蛋白。NF1基因的完全或半合子缺失会导致雪旺细胞和肥大细胞中Ras活性的增加，并伴随下游效应物的激活，从而促进增殖，改变细胞形状和运动。最近，我们发现在nf1缺陷肥大细胞中，p21激活的激酶在激活erk介导的增殖和p38介导的Ras下游运动通路中发挥重要作用。我们假设Pak功能的丧失也会减少NF1缺陷雪旺细胞中关键Ras效应通路的激活，从而可能使NF1患者受益。我们提出了三个目标：1)我们将确定肥大细胞中影响细胞运动的A组Paks的关键底物；2)利用药理学和遗传学手段使来自nf1缺陷小鼠的雪旺细胞中的Paks失活，我们将确定Pak功能的丧失是否会逆转MAPK的激活和体外细胞骨架的改变；3)我们将发生恶性周围神经鞘肿瘤的Krox20-cre/Nf1flox/-小鼠与Pak1敲除的小鼠杂交，或将这种NF1小鼠与Pak1-/-骨髓细胞移植，以确定Pak1的缺失是否会影响疾病进展，无论是全局的还是骨髓来源细胞中的。这些建议的研究不仅将增加我们对主要癌症相关信号通路的理解，而且可以确定Paks作为治疗干预这种其他无法治疗的疾病的合适靶点。