MECHANISMS OF CLONAL DOMINANCE IN PNH

PNH 中克隆优势的机制

• 批准号: 2633986
• 负责人: ROBERT A BRODSKY
• 金额: $ 7.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2633986
• 关键词: NOD mouse; SCID mouse; apoptosis; blood disorder chemotherapy; cellular pathology; ceramides; clinical research; gene mutation; human subject; human therapy evaluation; molecular pathology; paroxysmal nocturnal hemoglobinuria; sphingomyelin phosphodiesterase; transfection

The principal investigator's immediate goal is to develop into a clinician/scientist capable of conducting independent basic research in the field of hematopoiesis. He is particularly interested in the study of bone marrow failure states, especially paroxysmal nocturnal hemoglobinuria (PNH). His long-term goal is to utilize his extensive laboratory and clinical training to develop novel and effective therapies for aplastic anemia, PNH and myelodysplasia. To accomplish these goals the PI will spend the majority of his time in the laboratory to uncover the molecular and cellular factors that contribute to PNH and other bone marrow failure states. He will also be involved with these patients in the clinic and develop novel therapeutic protocols based on his laboratory findings. Specifically, his laboratory research shows that the genetic defect in PNH (mutation of a gene termed PIG-A) confers a survival advantage to PNH cells by rendering them resistant to apoptotic death, similar to other anti-apoptotic oncogenes. The mechanism by which these cells acquire cellular resistance to apoptosis appears to result from insufficient quantities of the lipid ceramide. Based on his laboratory findings demonstrating that the biology of PNH is similar to other hematologic malignancies, i.e., inhibited apoptosis, he has begun treating PNH patients with cytotoxic chemotherapy. Preliminary results have demonstrated dramatic clinical improvement, and show this approach can induce a complete remission, even in end-stage patients. Understanding the mechanism of cellular resistance to apoptosis that results from PIG-A mutations will give greater insight into the clonal dominance observed in PNH and possibly other malignancies. Furthermore, these preclinical studies should lead to novel therapeutic approaches for PNH.

主要研究者的近期目标是发展成一个 临床医生/科学家能够进行独立的基础研究 造血的领域。 他对这项研究特别感兴趣 骨髓衰竭状态，尤其是阵发性夜间 血红蛋白尿（PNH）。 他的长期目标是利用他的广泛 实验室和临床培训以开发新颖有效 性质贫血，PNH和骨髓增生性的疗法。 完成 这些目标PI将花费大部分时间在实验室 发现有助于PNH的分子和细胞因子 其他骨髓衰竭状态。 他还将参与这些 诊所的患者并根据 他的实验室发现。 具体来说，他的实验室研究表明 PNH中的遗传缺陷（称为pig-a的突变）赋予 PNH细胞的生存优势通过使它们具有抵抗力 凋亡死亡，类似于其他抗凋亡癌基因。 这 这些细胞获得细胞抗凋亡的机制 似乎是由于脂质神经酰胺数量不足所致。 根据他的实验室发现，证明了PNH的生物学 类似于其他血液系统恶性肿瘤，即抑制凋亡， 他已经开始治疗细胞毒性化学疗法的PNH患者。 初步结果表明临床改善，并且 证明这种方法也可以诱导完全缓解，即使在末期 患者。 了解细胞阻力的机制 猪A突变导致的凋亡将提供更大的洞察力 进入PNH和其他可能的克隆主导地位 恶性肿瘤。此外，这些临床前研究应导致 PNH的新型治疗方法。