REGULATION OF APOPTOSIS IN AIDS RELATED KAPOSIS SARCOMA

描述：卡波西博士肉瘤（KS）被认为是最常见的 艾滋病患者的肿瘤。 由于艾滋病患者的寿命更长， 治疗和减少他们的HIV-1病毒载量和机会 感染，KS变得越来越常见，医生的问题。 的 KS的发病机制复杂而不清楚。 细胞因子产生， 免疫抑制和HIV相关蛋白都被认为是 然而，这些因素中没有一个能够单独地 解释这种疾病的发病机制。 在本提案中，我们将联合收割机 这些进展与我们观察到KS肿瘤细胞在体外和体内 过表达抗凋亡蛋白Bcl-x。 目前尚不清楚， KS的发病机制中涉及到与KS相关的蛋白质， 假设细胞存活蛋白的过度表达有助于 KS肿瘤的出现或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， 的KS。 我们将首先定义KS中表达的糖尿病相关蛋白 肿瘤细胞在体外和体内，并扩大研究，包括 内皮细胞（EC，KS中可能的祖细胞）和转化的 ECs（T-ECs）创建细胞凋亡蛋白的全面图片 在一系列可能代表KS进展的细胞中表达 (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，我们将专注于确定如何特定的细胞 存活基因产物被调节，其功能意义KS 肿瘤细胞，并确定这种增加是否有助于其 长寿和逃避免疫监视。 然后我们将其扩展到 体外数据，并使用一种 用于致瘤性测定的具有完全人成分的KS的体内模型。 通过在未来5年内完成这3个目标，我们将取得重大进展， 在了解肿瘤过程中所涉及的进展 KS的发病机制，并获得新的分子见解，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.