NF Center: from animal models to therapeutics

神经纤维瘤中心：从动物模型到治疗学

基本信息

批准号：
8533025
负责人：
Luis Fernando Parada
金额：
$ 124.48万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-20 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8533025
关键词：
Administrator Adult Animal Model Appearance Award Axilla Biological Biomedical Research Blood Vessels Breeding Budgets Cell Communication Cell Lineage Cell Proliferation Cells Chemicals Clinic Clinical Treatment Clinical Trials Cognitive deficits Collaborations Common Neoplasm Competence Development Disease Embryo Transfer Ensure Equipment Equipment and Supplies Ethical Issues Ethics Etiology Event Expenditure FDA approved Faculty Freckles Funding Genes Genetic Genotype Grant Hereditary Disease Human Human Resources Incidence Individual Inguinal region Knockout Mice Laboratory Animals Lead Live Birth Maintenance Malignant Neoplasms Malignant Peripheral Nerve Sheath Tumor Methods Modeling Molecular Mouse Strains Mus Muscle function Mutation NF1 gene NF1 related tumorigenesis Nerve Neural Crest Neural tube Neurofibromatosis 1 Neurofibromatosis Type 1 Protein Outcome Pathologic Pathology Patients Pericytes Peripheral Peripheral Nervous System Phenotype Plexiform Neurofibroma Principal Investigator Quail RNA Interference Radioisotopes Research Research Personnel Resources Role Schwann Cells Series Signal Transduction Skin Source System Tamoxifen Techniques Testing Therapeutic Time Training Training Programs Transgenic Animals Transgenic Mice Transgenic Organisms Tumor Tissue United States National Institutes of Health Vascular Diseases Vascular Smooth Muscle Work base cell growth dermal neurofibroma experience hazard high throughput screening insight mast cell meetings mouse model multidisciplinary neoplastic cell neurofibroma novel pre-clinical pre-doctoral precursor cell programs public health relevance small molecule success therapeutic target therapy development tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): In this application, entitled: NF: from animal models to therapeutics, we are requesting funds for continued support of the NF Center. We build on our preceding success in exploiting animal models to gain novel insight into tumor etiology and revealing the mast cell as a therapeutic target that is now in clinical trials. The Center supports a series of highly interactive and multidisciplinary studies aimed at (1) delineating the mechanisms underlying the two most common tumors in NF1: dermal and plexiform neurofibromas and (2) dissecting the unknown functions of neurofibromin in regulating adult endothelial and vascular smooth muscle function - two cell lineages critical for establishment of the tumor vasculature in neurofibromas, and in the development of NF1 vasculopathies. The Center is organized into a small Administrative Core, a Transgenic/Animal Core, and four Projects. The Transgenic/Animal Core (PI, Luis F. Parada) is responsible for breeding transgenic and knockout mice, genotyping, and for developing or importing additional mouse strains. Project 1 (PI, Luis F. Parada) is a continuation of a productive effort to study the molecular and cellular mechanisms by which NF1 mutation engenders plexiform neurofibromas and malignant peripheral nerve sheath tumors. Project 2 (PI, D. Wade Clapp) focuses on the signaling mechanisms that promote interplay between Nf1-/- Schwann cells and different heterozygous cell lineages identified in the tumor microenvironment in neurofibroma development and targeting these cell-cell interactions with FDA-approved therapeutics. Project 2 will also utilize human cells isolated from NF1 patients to verify that the observations in the murine model are faithfully recapitulated in the human system as a preclinical platform to identify therapeutic targets within the neurofibroma microenvironment. Project 3 (PI, David Ingram) will study the role of Nf1 in controlling endothelial and vascular smooth muscle/pericyte function. Project 4 (PI, Lu Q. Le) will investigate the etiology of dermal neurofibromas in mouse and proposes a clinical trial for treatment of human patients. Project 4 also proposes the establishment of a comprehensive NF1 clinic. Together, the proposed program of research promises to contribute to a better understanding of NF1-associated tumorigenesis at the molecular, cellular, and systems levels.

描述（由申请人提供）：在此应用程序中，标题为：NF：从动物模型到治疗学，我们要求资金继续支持NF中心。我们基于在利用动物模型以获得对肿瘤病因的新颖洞察力并揭示肥大细胞作为现在正在临床试验中的治疗靶点的新知识的基础上。该中心支持一系列高度互动和多学科的研究，旨在（1）描述NF1中两个最常见肿瘤的基础机制：真皮和丛生的神经纤维瘤，以及（2）在调节成人内皮和血管平滑肌肉功能中的神经纤维素的未知功能 - 剖析神经纤维纤维的未知功能 - 两种抑制作用 - 两种肿瘤 - 两种抑制作用 - 两种基于成人的内皮纤维化效果 - 神经纤维瘤，以及NF1血管疾病的发展。该中心被组织成一个小的行政核心，一个转基因/动物核心和四个项目。转基因/动物核心（PI，Luis F. Parada）负责繁殖转基因和基因敲除小鼠，基因分型，以及开发或进口其他小鼠菌株。项目1（PI，Luis F. Parada）是研究分子和细胞机制的持续努力，NF1突变引起了神经纤维瘤和恶性周围神经鞘瘤。项目2（PI，D。WadeClapp）着重于促进NF1 - / - Schwann细胞之间相互作用的信号传导机制和在神经纤维瘤发育中鉴定出的不同杂合细胞谱系，并针对这些细胞细胞相互作用，这些谱系与FDA批准的治疗剂相互作用。项目2还将利用从NF1患者中分离出来的人类细胞来验证鼠模型中的观察结果是否在人类系统中忠实地概括为临床前平台，以鉴定神经纤维瘤微环境中的治疗靶标。项目3（PI，David Ingram）将研究NF1在控制内皮和血管平滑肌/周细胞功能中的作用。项目4（Pi，Lu Q. Le）将研究小鼠皮肤神经纤维瘤的病因，并提出一项治疗人类患者的临床试验。项目4还提议建立全面的NF1诊所。共同提议的研究计划将有望更好地理解分子，细胞和系统水平上与NF1相关的肿瘤发生。