Development and Maintenance of Thymic Epithelial Microenvironments

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。 公共卫生相关性：与胸腺在获得性免疫所需的T细胞发育中的关键重要性相反，胸腺在生命的相对早期经历了严重的萎缩。胸腺变性在人类青春期开始时就很明显，并导致T细胞功能和抗感染能力的显著丧失。骨髓移植虽然可能治愈许多形式的癌症和非恶性血液疾病，但由于移植前治疗诱导的胸腺损伤导致T细胞功能长期丧失，因此通常导致潜在的致命感染和恶性复发。本研究通过鉴定能够重建功能性胸腺组织的成体干细胞来解决关键的未满足的临床需求，以增强胸腺重建，所述成体干细胞可用于治疗策略，以在BMT或其他细胞消融治疗后最小化损伤并加速胸腺功能的恢复。

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.