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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.

项目总结: