Role of c-Mpl in HIV-1 Induced Cytopenias

描述（由申请人提供）：HIV-1感染和HAART可导致细胞减少，影响患者的血细胞形成和免疫反应。该项目将利用移植了人类胎儿胸腺和肝脏组织的SCID小鼠（SCID-hu Thy/Liv）来研究HIV-1和HAART诱导的多系造血抑制机制，并测试细胞因子和药物治疗。PI将重点研究造血细胞因子，血小板生成素（Tpo）及其受体（c-mpl），因为它们是多系造血的重要效应器。c-mpl主要与CD34+细胞向巨核细胞的分化有关。建议的具体目的如下：(1)在存在或不存在HAART的情况下，确定从HIV-1感染的SCID-hu小鼠中获得的CD34+c-mpl+与CD34+c-mpl-细胞在SCID-hu受体Thy/Liv植入物中重新植入和重建后的造血恢复效果；(2)确定细胞因子治疗和HAART对CD34+c-mpl+与CD34+c-mpl-细胞的c-mpl表达和造血恢复效果的影响。(3)确定携带人c-mpl基因的慢病毒载体转导CD34+细胞植入SCID-hu Thy/Liv植入物和细胞因子治疗是否有助于HIV-1感染的多系造血。

DESCRIPTION (provided by applicant): HIV-1 infection and HAART can lead to cytopenias affecting blood cell formation and immune responses in infected patients. The PI will utilize the SCID mouse transplanted with human fetal thymus and liver tissues (SCID-hu Thy/Liv) to study the mechanisms of HIV-1 and HAART induced multilineage hematopoietic inhibition and testing cytokines and drug therapies. The PI will focus this research investigation on the hematopoietic cytokine, thrombopoietin (Tpo) and its receptor (c-mpl) since they are important effectors of multilineage hematopoiesis. The c-mpl is primarily associated with differentiation of CD34+ cells into megakaryocytes. The Specific aims of the proposal are as following: (1) to determine hematopoietic revival effects of CD34+c-mpl+ versus CD34+c-mpl- cells obtained from HIV-1 infected SCID-hu mouse in the presence or absence of HAART, following re-engraftment and reconstitution of these CD34+ cell subsets in the Thy/Liv implants of SCID-hu recipients, (2) to determine the effects of cytokine treatment and HAART on the c-mpl expression and hematopoietic revival effects of CD34+c-mpl+ versus CD34+c-mpl- cells, and (3) to determine if engraftment of CD34+ cells transduced with a lentiviral vector carrying human c-mpl gene into the SCID-hu Thy/Liv implants and cytokine treatment will contribute to multilineage hematopoiesis in HIV-1 infection.