Development and Maintenance of Thymic Epithelial Microenvironments

说明(申请人提供)：发展和维持一个功能正常的免疫系统有赖于一个组织和功能正常的胸腺。胸腺上皮细胞(TECs)构成胸腺的结构，负责维持胸腺的主要功能。骨髓移植可以治愈多种形式的血源性癌症以及非恶性血液疾病。不幸的是，尤其是在成年患者中，骨髓移植会损害胸腺，特别是TECs，导致抗击感染和癌症的能力降低。各种组织中的干细胞都是通过它们非常缓慢的分裂能力来鉴定的，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用于鉴定和纯化活体组蛋白2B-绿色荧光蛋白标记的干细胞，并成功地用于鉴定和纯化皮肤干细胞，该系统已被用于纯化胸腺上皮干细胞。初步结果表明，外科手术将这些细胞转移到肾被膜下，可以形成功能性胸腺组织。这项研究的目的将是：1)进一步鉴定最近发现的具有改造胸腺组织的能力的胸腺上皮干细胞；2)了解控制成人胸腺干细胞维持的信号和细胞间的相互作用；3)在骨髓移植的小鼠模型中测试胸腺干细胞和最近开发的干细胞株的能力，以促进胸腺功能的恢复。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骨髓移植而发生的胸腺过早退化。从发展的角度来看，这项研究将允许PI继续培训服务不足的研究型学生，同时提高实验室的科学生产率和出版出版物的影响，使少数族裔服务机构的研究人员能够更有竞争力地获得NIH的支持。 与公共卫生相关：与胸腺在发展适应性免疫所需的T细胞中的关键重要性相矛盾的是，胸腺在生命的相对早期经历了严重的萎缩。胸腺退化明显始于人类青春期，并导致T细胞功能和抗感染能力的显著丧失。骨髓移植虽然有可能治愈多种形式的癌症和非恶性血液疾病，但往往会导致潜在的致命感染和恶性复发，原因是移植前治疗导致胸腺受损导致T细胞功能长期丧失。这项研究解决了一个关键的临床需求，即通过鉴定能够改造功能性胸腺组织的成人干细胞来增强胸腺重建，这种干细胞可以用于治疗策略，既减少损害，又加速骨髓移植或其他细胞切除治疗后胸腺功能的恢复。

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.