HIV-INFECTED GI MESENCHYMAL CELLS MIMIC KAPOSI'S SARCOMA

人类免疫缺陷病毒-1（HIV-1）参与的机制 在卡波西肉瘤（KS）发展和血管细胞调节中 生长在KS损伤形成中的作用尚不清楚。这是 部分原因是这种疾病的体外模型 因此，迄今为止，主要集中在KS来源的细胞 在起始事件发生后很久才发生的病变。我们 最近发现，人类胃肠道（GI）感染 粘膜下间充质（SM）细胞（其包括血管细胞和 血管细胞前体）与HIV-1导致细胞群与 异常生长特性，增加内皮细胞的合成， 成血管细胞标志物和血管生成因子的释放。基于那些 我们目前的假设是，HIV-1感染的血管 和其他来源于GI间充质组织的细胞是一种模型， 起始事件、血管生成的诱导以及血管生成的其他特征。 KS的发展。本申请的目的是追求， 通过实现以下目标，在本RFA框架内实现假设 具体目标：[1]培养、克隆和表征血管和其他 SM衍生的细胞; [2]测试各种HIV毒株以识别毒株- 个体之间、GI器官部位之间、 或诱导KS样表型; [3]比较生长 细胞的特性、血管生成和致瘤特性 接种HIV后，对照培养物和KS衍生培养物 病变; [4]检测合成或反应中的任何差异， 生长控制分子; [5]确定达特基因产物是否可以 直接导致SM细胞表现得像KS细胞; [6]评估 微生物辅助因子（特别是CMV和支原体） 调节病毒复制和/或KS表型。这些研究 不仅对理解生物学， 知识共享的发展，但也有多个方面的增长和 在该模型系统中调节血管细胞的分化。 这些工作可能导致潜在的预防或治疗应用 这种疾病通常与艾滋病有关， 心血管疾病

Mechanisms by which human immunodeficiency virus-1 (HIV-1) is involved in Kaposi's sarcoma (KS) development and regulation of vascular cell growth in the formation of a KS lesion are not understood. This is partially due to the fact that in vitro models for the disease have thusfar been limited, and primarily focused on cells derived from KS lesions which occur long after the initiating events have occurred. We have recently found that infection of human gastrointestinal (GI) submucosal mesenchymal (SM) cells (which includes vascular cells and vascular cell precursors) with HIV-1 led to cell populations with abnormal growth properties, increased synthesis of endothelial cell and angioblast markers, and release of angiogenic factors. Based on those observations, our current hypothesis is that HIV-1 infection of vascular and other cells derived from GI mesenchymal tissue is a model for the initiation events, induction of angiogenesis, and other features of the development of KS. The purpose of this application is to pursue that hypothesis within the framework of this RFA by achieving the following specific aims: [1] Culture, clone, and characterize vascular and other SM-derived cells; [2] Test various strains of HIV to identify strain- specific differences in infectivity among individuals, GI organ sites, or induction of the KS-like phenotype; [3] Compare the growth characteristics, angiogenic and tumorigenic properties of the cells after HIV inoculation to control cultures and cultures derived from KS lesions; [4] Detect any differences in the synthesis of, or response to, growth-controlling molecules; [5] Determine if the tat gene product can directly cause SM cells to behave like KS cells; [6] Assess the role of microbiological co-factors (particularly CMV and Mycoplasma) in modulating virus replication and/or the KS phenotype. These studies have major potential implications towards understanding not only the biology of KS development, but also multiple facets by which the growth and differentiation of vascular cells is regulated in this model system. Such work may lead to potential applications for prevention or treatment of this affliction which is commonly associated with AIDS as well as cardiovascular diseases.