Development and Maintenance of Thymic Epithelial Microenvironments

胸腺上皮微环境的发展和维持

• 批准号: 8338776
• 负责人: MARK PEZZANO
• 金额: $ 38.25万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338776
• 关键词: Address; Adipocytes; Adult; Architecture; Atrophic; Biological Models; Blood; Bone Marrow; Bone Marrow Transplantation; Cancer Patient; Cell Communication; Cell Line; Cell Maintenance; Cell physiology; Cell surface; Cells; Characteristics; Chondrocytes; Clinical; Coculture Techniques; Development; Disease; Engraftment; Epithelial; Exhibits; Fluorescence; Gene Expression; Genes; Genetically Engineered Mouse; Growth; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Histones; Homeostasis; Human; Immune; Immune system; In Vitro; Infection; Injection of therapeutic agent; Integrins; Kidney; Label; Lead; Life; Location; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Mesenchymal; Mesenchymal Stem Cells; Minority-Serving Institution; Morbidity - disease rate; Mouse Strains; Natural regeneration; Non-Malignant; Nude Mice; Operative Surgical Procedures; Osteoblasts; Patients; Phenotype; Population; Population Heterogeneity; Productivity; Property; Proteins; Puberty; Publications; Recovery; Recruitment Activity; Relapse; Reporter; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Skin; Sorting - Cell Movement; Stem Cell Factor; Stem cell transplant; Stem cells; Structure; Students; T-Cell Development; T-Lymphocyte; TACSTD2 gene; Testing; Thymic Tissue; Thymic epithelial cell; Thymus Gland; Time; Tissues; Training; Transgenic Mice; Transgenic Model; Translations; Transplantation; United States National Institutes of Health; adaptive immunity; adult stem cell; base; bone; cancer therapy; capsule; design; fighting; functional loss; immune function; improved; in vivo; inhibitor/antagonist; mouse model; novel; pluripotency; postnatal; premature; progenitor; reconstitution; response; self-renewal; stem cell population; treatment strategy

DESCRIPTION (provided by applicant): Development and maintenance of a properly functioning immune system is dependent upon a properly organized and functioning thymus. Thymic epithelial cells (TECs) make up the structure of the thymus and are responsible for the maintaining its primary functions. Bone marrow transplants can cure many forms of blood-derived cancers as well as non-malignant blood disorders. Unfortunately, particularly in adult patients, bone marrow transplants damage the thymus and in particular TECs resulting in a reduced capacity to fight infection and cancer. Stem cells in a variety of tissues have been identified by their capacity to divide very slowly, the so-called "label retaining cells" (LRCs). A novel genetically engineered mouse model system, which allows identification and purification of viable Histone 2B-green fluorescence protein tagged stem cells and was successfully used to identify and purify skin stem cells, has been used here to purify thymic epithelial stem cells. Preliminary results show that surgical transfer of these cells under the kidney capsule results in the formation of functional thymic tissue. The aims of this study will be to: 1) further characterie the recently identified thymic epithelial stem cells with the ability to reform thymic tissue; 2) understand the signals and cell to cell interactions that control the maintenance of adult thymic stem cells; 3) test the capacity of thymic stem cells and recently developed stem cell lines to enhance the recovery of thymic function in a mouse model of bone marrow transplant. These studies will be instrumental in the design of new clinical strategies to counteract thymic involution as well as the premature thymic degeneration that occurs in response to cancer treatments and BMT. From a developmental standpoint this study will allow the PI to continue to train underserved research students, while enhancing both the scientific productivity of the lab and the impact of the publications produced, enabling a researcher at a minority serving institution to be more competitive for NIH support. PUBLIC HEALTH RELEVANCE: In paradox to the critical importance of the thymus in the development of T cells required for adaptive immunity, the thymus undergoes profound atrophy relatively early in life. Thymic degeneration is evident starting at puberty in humans and contributes to a significant loss of T cell function and the capacity to fight infection. Bone marrw transplants, while potentially curative for many forms of cancer and non-malignant blood disorders, often result in potentially lethal infections and malignant relapse, due to a prolonged loss of T cell function resulting from damage to the thymus induced by pre-transplant therapies. This study addresses a critical unmet clinical need to enhance thymic reconstitution through the identification of adult stem cells capable of reforming functional thymic tissue that may be used in treatment strategies to both minimize damage and hasten recovery of thymic function following BMT or other cytoablative therapies.

描述（由申请人提供）：功能正常的免疫系统的发育和维持依赖于组织正确且功能正常的胸腺。胸腺上皮细胞 (TEC) 构成胸腺的结构并负责维持其主要功能。骨髓移植可以治愈多种形式的血液癌症以及非恶性血液疾病。不幸的是，特别是在成年患者中，骨髓移植会损害胸腺，特别是 TEC，导致抵抗感染和癌症的能力下降。多种组织中的干细胞因其分裂速度非常缓慢的能力而被鉴定，即所谓的“标记保留细胞”（LRC）。一个 新型基因工程小鼠模型系统可鉴定和纯化活的组蛋白 2B 绿色荧光蛋白标记的干细胞，并成功用于鉴定和纯化皮肤干细胞，该系统已用于纯化胸腺上皮干细胞。初步结果表明，通过手术将这些细胞转移到肾被膜下会导致功能性胸腺组织的形成。本研究的目的是：1）进一步鉴定最近发现的具有改造胸腺组织能力的胸腺上皮干细胞； 2）了解控制成体胸腺干细胞维持的信号和细胞间相互作用； 3）测试胸腺干细胞和最近开发的干细胞系在骨髓移植小鼠模型中增强胸腺功能恢复的能力。这些研究将有助于设计新的临床策略，以对抗胸腺退化以及因癌症治疗和 BMT 而发生的过早胸腺退化。从发展的角度来看，这项研究将使 PI 能够继续培训服务不足的研究生，同时提高实验室的科学生产力和所发表出版物的影响力，使少数族裔服务机构的研究人员在获得 NIH 支持时更具竞争力。 公共健康相关性：与胸腺在适应性免疫所需的 T 细胞发育中的至关重要性相反，胸腺在生命的早期就经历了严重的萎缩。胸腺变性在人类青春期开始就很明显，并导致 T 细胞功能和抵抗感染能力的显着丧失。骨髓移植虽然可以治愈多种癌症和非恶性血液疾病，但由于移植前治疗引起的胸腺损伤导致 T 细胞功能长期丧失，因此常常导致潜在的致命感染和恶性复发。这项研究解决了一个关键的未满足的临床需求，即通过鉴定能够改造功能性胸腺组织的成体干细胞来增强胸腺重建，这些细胞可用于治疗策略，以最大限度地减少 BMT 或其他细胞清除疗法后的损伤并加速胸腺功能的恢复。