REGULATION OF APOPTOSIS IN AIDS RELATED KAPOSIS SARCOMA

描述：卡波西博士肉瘤(KS)是公认的最常见的 艾滋病患者中的肿瘤。由于艾滋病患者活得更好，他们的寿命更长 治疗和减少其HIV-1病毒载量和机会性 随着感染的增加，KS对医生来说正变得越来越常见和有问题。这个 KS的发病机制复杂，目前尚不清楚。细胞因子的产生， 免疫抑制和艾滋病毒相关蛋白都被提出为 在KS中很重要；然而，这些因素中没有一个单独能够 解释这种疾病的发病机制。在这个提案中，我们结合了 这些进展与我们在体外和体内观察到的KS肿瘤细胞 过表达抗细胞凋亡蛋白Bclx。目前尚不清楚是否 细胞凋亡相关蛋白参与了KS的发病机制，我们 假设细胞生存蛋白的过度表达有助于 KS瘤的出现、生存优势和免疫逃逸 因此，细胞在发病机制中起着至关重要的作用 KS.我们将首先定义KS中表达的与细胞凋亡相关的蛋白 体外和体内的肿瘤细胞，并扩大研究范围以包括 内皮细胞(ECs，KS中可能的祖细胞)并转化为 ECS(T-ECs)将创建一幅全面的凋亡蛋白图景 在一系列细胞中表达，可能代表向KS的进展 (ECS-T-EC-KS肿瘤细胞)。一旦我们有了一个连贯的画面， 蛋白质的表达，我们将专注于确定特定的细胞如何 生存基因产物的调控及其功能意义 并确定这种增加是否有助于它们的 免疫监视的长寿和逃避。然后我们将把它扩展到 体外数据，并使用In检查功能结果的准确性 用于致瘤性分析的全人成分KS活体模型。 通过在未来5年实现这3个目标，我们将使 肿瘤发生、发展过程的研究进展 KS的发病机制，并获得新的分子认识，以帮助发展 针对KS肿瘤细胞中的凋亡相关蛋白的新疗法。 这种新的治疗选择对于经常 发展出这种致命的肿瘤。

DESCRIPTION: Dr. Kaposi's sarcoma (KS) is recognized as the most common tumor in AIDS patients. As AIDS patients are living longer due to better treatment and reduction of their HIV-1 viral load and opportunistic infections, KS is becoming more common and problematic for physicians. The pathogenesis of KS is complex and unclear. Cytokine production, immunosuppression and HIV-related proteins have all been proposed as important in KS; however, none of these factors alone has been able to explain the pathogenesis of this disease. In this proposal, we combine these advances with our observation that KS tumor cells in vitro and in vivo overexpress the anti-apoptotic protein, Bcl-x. It is currently unknown if apoptosis-related proteins are involved in the pathogenesis of KS, and we hypothesize that overexpression of cell survival proteins contributes to the emergence of, or survival advantage and immunologic escape of, KS tumor cells thereby functioning in a critically important role in the pathogenesis of KS. We will first define the apoptosis-related proteins expressed in KS tumor cells both in vitro and in vivo and expand the studies to include endothelial cells (ECs, the likely progenitor cell in KS) and transformed ECs (T-ECs) to create a comprehensive picture of apoptosis proteins expressed in a series of cells that likely represent the progression to KS (ECs - T-EC - KS tumor cells). Once we have a coherent picture of which proteins are expressed, we will focus on determining how specific cell survival gene products are modulated and their functional significance KS tumor cells in vitro and determine if this increase contributes to their longevity and evasion of immunosurveillance. We will then extend this in vitro data and examine the veracity of the functional results using an in vivo model of KS with entirely human constituents for tumorigenicity assays. By completing these 3 aims over the next 5 years, we will make significant advancements in understanding neoplastic processes involved in the pathogenesis of KS, and gain new molecular insight to aid in the development of novel therapies targeting apoptosis-related proteins in KS tumor cells. Such new treatment options are important for AIDS patients who frequently develop this deadly neoplasm.