REGULATION OF APOPTOSIS IN AIDS RELATED KAPOSIS SARCOMA

艾滋病相关卡波西斯肉瘤中细胞凋亡的调节

基本信息

批准号：
6513403
负责人：
Kimberly E Foreman
金额：
$ 11.57万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-03-01 至 2004-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6513403
关键词：
REGULATION APOPTOSIS AIDS RELATED KAPOSIS

项目摘要

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.

描述：Kaposi博士的肉瘤（KS）被认为是最常见的艾滋病患者的肿瘤。随着艾滋病患者的寿命，由于更好治疗和减少HIV-1病毒载荷和机会性感染，对于医生而言，KS变得越来越普遍和问题。这 KS的发病机理是复杂且不清楚的。细胞因子生产，已提出了免疫抑制和与HIV相关的蛋白在KS中很重要；但是，仅这些因素都无法解释该疾病的发病机理。在此提案中，我们结合了通过观察到KS肿瘤细胞体外和体内的这些进展过表达抗凋亡蛋白Bcl-X。目前未知是否与凋亡相关的蛋白质参与KS的发病机理，我们假设细胞存活蛋白的过表达有助于 KS肿瘤的出现或生存优势或免疫学逃生细胞因此在发病机理中起着至关重要的作用 KS。我们将首先定义在KS中表达的凋亡相关蛋白体外和体内肿瘤细胞，并扩大研究以包括内皮细胞（ECS，Ks中可能的祖细胞）并转化 ECS（T-EC）创建凋亡蛋白的全面图片以一系列可能代表KS进展的细胞表达（ECS -T -EC -KS肿瘤细胞）。一旦我们有一幅连贯的图片表达蛋白质，我们将重点放在确定特定细胞生存基因产物被调制，其功能意义ks 体外肿瘤细胞，并确定这种增加是否有助于其寿命和逃避免疫监视。然后我们将其扩展到体外数据并使用IN检查功能结果的准确性具有全人类成分的KS的体内模型，用于肿瘤性测定。通过在接下来的5年内完成这三个目标，我们将发挥重要作用理解涉及的肿瘤过程的进步 KS的发病机理，并获得新的分子见解以帮助发展针对KS肿瘤细胞中凋亡相关蛋白的新型疗法。这种新的治疗选择对于经常的艾滋病患者很重要发展这种致命的肿瘤。