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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

基本信息

批准号：
8403560
负责人：
JONATHAN CHERNOFF
金额：
$ 37.99万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
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/8403560
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 small molecule therapeutic target tumor tumorigenesis

项目摘要

Title: p21-activated kinases as new therapeutic targets in neurofibromatosis type 1. Project Summary: 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.

题目：p21活化激酶作为1型神经纤维瘤病的新治疗靶点。