MECHANISMS OF CLONAL DOMINANCE IN PNH

首席调查员的直接目标是发展成为一名 能够进行独立基础研究的临床医生/科学家 造血领域。他对这项研究特别感兴趣 骨髓衰竭状态，尤其是阵发性夜间发作 血红蛋白尿(PNH)。他的长期目标是利用他广泛的 实验室和临床培训，开发新的和有效的 再生障碍性贫血、PNH和骨髓发育不良的治疗。要完成 这些目标PI将把他的大部分时间花在实验室里 为了揭示导致PNH的分子和细胞因素， 其他骨髓衰竭状态。他还将参与这些 临床上的患者，并开发基于 他的实验室发现。具体来说，他的实验室研究表明 PNH(一种名为PIG-A的基因突变)的遗传缺陷 PNH细胞的生存优势是使它们对 凋亡性死亡，类似于其他抗凋亡癌基因。这个 这些细胞获得细胞凋亡抵抗力的机制 似乎是由于脂质神经酰胺的数量不足造成的。 根据他的实验室发现，PNH的生物学 与其他血液系统恶性肿瘤相似，即细胞凋亡受抑， 他已经开始用细胞毒性化疗治疗PNH患者。 初步结果显示，临床症状有了显著改善， 证明这种方法可以导致完全缓解，即使是在晚期 病人。了解细胞抗药性的机制 PIG-A基因突变导致的细胞凋亡将提供更多的洞察力 转化为在PNH中观察到的克隆显性 恶性肿瘤。此外，这些临床前研究应该导致 PNH的新治疗方法。

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.