Role of c-Mpl in HIV-1 Induced Cytopenias

描述(申请人提供)：HIV-1感染和HAART可导致细胞减少症，影响感染患者的血细胞形成和免疫反应。PI将利用移植人胎胸腺和肝组织的SCID小鼠(SCID-Hu Thy/Liv)来研究HIV-1和HAART诱导的多系造血抑制的机制，并测试细胞因子和药物治疗。由于血小板生成素(TPO)及其受体(c-MPL)是多系造血的重要效应因子，因此PI将重点研究造血细胞因子TPO及其受体(c-MPL)。C-MPL主要与CD34+细胞向巨核细胞分化有关。该建议的具体目的如下：(1)确定CD34+c-MPL+与CD34+c-MPL-细胞在HAART存在或不存在的情况下，CD34+c-MPL+与CD34+c-MPL-细胞在有或不存在HAART的情况下的造血恢复效果，这些CD34+细胞亚群在SCID-Hu受者的Thy/Liv移植中重新植入和重建，(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的CD34+细胞植入SCID-Hu Thy/Liv植入体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.