Cell of Origin and the Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics

起源细胞和肿瘤微环境在神经纤维瘤发展和治疗中的作用

基本信息

批准号：
10469978
负责人：
Lu Le
金额：
$ 16.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-03 至 2024-01-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469978
关键词：
Address Adoption Adult Affect Animal Model Area Automobile Driving Biological Biological Models Biological Process Biology Body Surface Cell Lineage Cells Cellular biology Chronic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Cosmetics Cutaneous Development Disease Distress Emotional Employment Epigenetic Process Evaluation Evolution Genes Genetic Genetic Diseases Growth Human Human Genetics Impairment In Vitro Individual Infection Knowledge Life Link Live Birth Mediating Medical Modeling Mus Mutation Myelin Sheath Neoplastic Schwann Cell Nerve Nerve Fibers Neural Crest Neurofibromatoses Neurofibromatosis 1 Neurofibrosarcoma Neurophysiology - biologic function Numbness Operative Surgical Procedures Organ Other Genetics Pain Pathogenesis Patients Penetrance Peripheral Nerve Sheath Neoplasm Peripheral Nerves Pharmaceutical Preparations Phenotype Plexiform Neurofibroma Pre-Clinical Model Preclinical Drug Evaluation Preclinical Testing Pruritus Puberty Quality of life Research Research Proposals Role Schwann Cells Signal Transduction Skin Source Symptoms Testing Therapeutic Transplantation Tumor Suppressor Genes Tumor stage Work cell type chronic pain defined contribution in vivo induced pluripotent stem cell inhibitor innovation mouse model nervous system disorder neurofibroma new therapeutic target novel novel therapeutic intervention physical symptom pre-clinical prevent psychosocial response social stem cell technology therapeutic evaluation therapeutic target therapy development tissue culture trait tumor tumor microenvironment tumor progression

项目摘要

Project Summary: Neurofibromatosis type 1 (NF1) is a genetic disorder that affects around 1:3000 live births. While the disease has nearly 100% penetrance in patients, NF1 has a diverse spectrum of manifestations. Hallmark traits of the disease include café-au-lait macules, cutaneous neurofibromas (cNF), plexiform neurofibromas (pNF) and malignant peripheral nerve sheath tumors (MPNST), among other symptoms. In NF1 patients, cNFs usually arise at puberty and beyond, can range widely in size and number, and can cause itching, pain, superficial infections as well as psychosocial and cosmetic burdens. Currently, there is no approved therapeutic option for cNFs aside from elective surgery. The development of new therapeutic approaches for cNF will require an understanding of the cNF cellular origin that can be used to elucidate mechanisms that underpin cNF formation and growth. While biallelic inactivation of NF1 in neoplastic Schwann cells is essential for cNF formation, it is not sufficient, pointing to the critical roles of other genetic or epigenetic changes as well as extrinsic signals from other cell types in the tumor microenvironment. While the field has made significant inroads towards our understanding of these tumors, there are still gaps in our knowledge of cNF pathogenesis that could be addressed by the adoption of a systemic approach to decipher all the biological steps in cNF development from the cell of origin to tumor stage to identify the “rate limiting step” that can be therapeutically targeted to prevent or delay cNF formation. Therefore, in this application, we propose a set specific aims to fill this knowledge gap: We will define the identity of the cNF cell of origin in mice that will guide us to identify the cells of origin for human cNF. We will next decipher how the cell of origin and the tumor microenvironment contribute to drive cNF initiation that will uncover its pathogenesis to delineate biological steps and mechanisms in tumor development as well as generating of preclinical models system that elucidate cNF biology and enable preclinical therapeutic testing.

项目概要： 1 型神经纤维瘤病 (NF1) 是一种遗传性疾病，影响约 1:3000 的活产儿。 NF1 在患者中的外显率接近 100%，具有多种标志性特征。疾病包括牛奶咖啡斑、皮肤神经纤维瘤（cNF）、丛状神经纤维瘤（pNF）和恶性周围神经鞘瘤 (MPNST) 等症状在 NF1 患者中通常会出现 cNF。出现于青春期及以后，其大小和数量范围广泛，可引起瘙痒、疼痛、浅表目前，尚无批准的治疗方案。除择期手术外，cNF 还需要开发新的治疗方法。了解 cNF 细胞起源，可用于阐明支持 cNF 形成的机制虽然肿瘤雪旺细胞中 NF1 的双等位基因失活对于 cNF 的形成至关重要，但它是还不够，指出其他遗传或表观遗传变化以及外在信号的关键作用来自肿瘤微环境中的其他细胞类型，而该领域已经在我们的研究领域取得了重大进展。尽管我们对这些肿瘤的了解仍然存在差距，但我们对 cNF 发病机制的了解仍然存在差距，这可能是通过采用系统方法来破译 cNF 发育的所有生物学步骤来解决从起源细胞到肿瘤阶段，以确定“限速步骤”，可以进行治疗靶向以预防因此，在本申请中，我们提出了一组具体目标来填补这一知识。间隙：我们将定义小鼠中 cNF 细胞的起源，这将指导我们识别细胞的起源接下来我们将破译细胞起源和肿瘤微环境如何促进驱动。 cNF 启动将揭示发病机制，描绘肿瘤的生物学步骤和机制开发和生成临床前模型系统，阐明 cNF 生物学并启用临床前治疗测试。