Development and Maintenance of Thymic Epithelial Microenvironments

胸腺上皮微环境的发展和维持

• 批准号: 8527705
• 负责人: MARK PEZZANO
• 金额: $ 32.36万
• 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/8527705
• 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; public health relevance; 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.

描述（由申请方提供）：正常功能的免疫系统的发育和维持依赖于正常组织和功能的胸腺。胸腺上皮细胞（TEC）构成了胸腺的结构，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来源的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，导致抗感染和癌症的能力降低。各种组织中的干细胞已经通过它们非常缓慢地分裂的能力来鉴定，即所谓的“标记保留细胞”（LRC）。一 一种新的基因工程小鼠模型系统，它允许鉴定和纯化活的组蛋白2B-绿色荧光蛋白标记的干细胞，并已成功地用于鉴定和纯化皮肤干细胞，已用于纯化胸腺上皮干细胞。初步结果表明，将这些细胞转移到肾包膜下可形成功能性胸腺组织。本研究的目的是：1）进一步鉴定具有改革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;第三章在小鼠骨髓移植模型中测试胸腺干细胞和最近开发的干细胞系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癌症治疗和BMT引起的胸腺过早变性。从发展的角度来看，这项研究将使PI继续培养服务不足的研究生，同时提高实验室的科学生产力和出版物的影响力，使少数民族服务机构的研究人员对NIH的支持更具竞争力。