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Strategy for Rescuing Primary Thymic Stromal Failure

原发性胸腺间质衰竭的挽救策略

基本信息

批准号：
7688534
负责人：
DONG-MING SU
金额：
$ 21.15万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-17 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688534
关键词：
22q11 Affect Antibodies Blood Bone Marrow Bone Marrow Transplantation CD8B1 gene Cell Count Cell Surface Proteins Cell physiology Defect Development DiGeorge Syndrome Disease Ectopic Thymus Engineering Epithelial Epithelial Cells Failure Fibroblasts Future Gene Mutation Generations Genes Hematopoietic Hematopoietic stem cells Human Immune system Immunodeficient Mouse Immunologic Deficiency Syndromes Kidney Knowledge Lead Ligands Maintenance Methods Modeling Mus Mutant Strains Mice Mutation Natural Killer Cells Natural regeneration Nude Mice Operative Surgical Procedures Organogenesis Patients Peripheral Process Production Proteomics Recruitment Activity Severe Combined Immunodeficiency Skin Source Stem cells Stromal Cells T-Cell Immunodeficiency T-Cell Receptor T-Lymphocyte Testing Therapeutic Thymectomy Thymic Tissue Thymic epithelial cell Thymus Gland Tissues Transplantation Undifferentiated Wild Type Mouse base capsule fetal high risk human subject immunopathology improved insight keratinocyte mouse model notch protein novel postnatal progenitor public health relevance

项目摘要

DESCRIPTION (provided by applicant): Primary T-lymphocyte (T-cell) immunodeficiency is mainly attributable to defects in thymus development because the thymus provides a unique microenvironment for development and maintenance of broadly reactive and self-restricted T cells and a diverse peripheral T-cell repertoire. Primary T-cell immunodeficiency caused by thymic organogenetic and thymic stromal cell (TSC) developmental failure, such as DiGeorge syndrome (DGS) which is likely caused by a mutation in the Tbx1 gene and human nude (HN) which is caused by a mutation in the Foxn1 gene, can be rescued by regenerating a de novo ectopic thymus using an ex vivo three-dimensional TSC network. However, the source of a safe, stable, and effective donor thymus becomes a problem because thymectomy during cardiothoracic surgery will cause profound problems in the donor's immune system. In order to obtain a safe, stable, and effective TSC network, we propose generating a de novo ectopic thymus under the kidney capsule by using various stromal cells in a mouse model. We will test engineered Notch ligand and Foxn1 over-expressing skin fibroblasts and keratinocytes from normal or Tbx1 mutant mice for generating a functional de novo thymus for DGS therapy detailed in our Aim 1. We will identify specific phenotypic markers from putative thymic epithelial progenitors through our novel Foxn1Neo/Neo and Foxn1Neo/+ mice by G418-selection culture; and then isolate and expand the putative thymic epithelial progenitors from wild-type thymus based on the specific thymic epithelial progenitor phenotypic markers for testing the strategy of HN therapy detailed in our Aim 2. The comprehensive knowledge obtained from the proposed studies will lay the groundwork to extend the study to human subjects in the future, and lead to the development of practical strategies against T-cell immunodeficiency caused by primary thymic organogenetic and/or TSC developmental failure. PUBLIC HEALTH RELEVANCE: We will test various stromal cells, including Notch ligand and Foxn1 over-expressing skin fibroblasts and keratinocytes from wild-type or Tbx1 mutant mice and isolate and expand the putative thymic epithelial progenitors from wild-type mice, for generating a functional de novo thymus for DiGeorge syndrome and human nude therapies in a mouse model.

描述（由申请人提供）：原发性T淋巴细胞（T细胞）免疫缺陷主要归因于胸腺发育缺陷，因为胸腺为广泛反应性和自限性T细胞和多种外周T细胞库的发育和维持提供了独特的微环境。由胸腺器官发生和胸腺基质细胞（TSC）发育失败引起的原发性t细胞免疫缺陷，如可能由Tbx1基因突变引起的DiGeorge综合征（DGS）和由Foxn1基因突变引起的human nude (HN)，可以通过使用离体三维TSC网络再生异位胸腺来拯救。然而，安全、稳定、有效的供体胸腺的来源成为一个问题，因为胸腺切除术在心胸外科手术中会对供体的免疫系统造成严重的问题。为了获得一个安全、稳定、有效的TSC网络，我们提出在小鼠模型中，利用各种基质细胞在肾包膜下再生异位胸腺。我们将从正常或Tbx1突变小鼠中测试工程化Notch配体和Foxn1过表达的皮肤成纤维细胞和角化细胞，以产生用于DGS治疗的功能性新生胸腺。我们将通过我们的新型Foxn1Neo/Neo和Foxn1Neo/+小鼠，通过g418选择培养，从推测的胸腺上皮祖细胞中鉴定特异性表型标记；然后根据特异性胸腺上皮祖细胞表型标记从野生型胸腺中分离和扩增推测的胸腺上皮祖细胞，以测试我们Aim 2中详细介绍的HN治疗策略。从拟议的研究中获得的全面知识将为将来将研究扩展到人类受试者奠定基础，并导致针对原发性胸腺器官发生和/或TSC发育失败引起的t细胞免疫缺陷的实用策略的发展。公共卫生相关性：我们将测试来自野生型或Tbx1突变小鼠的各种基质细胞，包括Notch配体和Foxn1过表达的皮肤成纤维细胞和角质形成细胞，并从野生型小鼠中分离和扩增假定的胸腺上皮祖细胞，以在小鼠模型中为digegeorge综合征和人类裸疗法生成功能新生胸腺。