MECHANISMS OF CLONAL DOMINANCE IN PNH

首席研究员的近期目标是发展成为一个 临床医生/科学家能够进行独立的基础研究， 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 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，以开发新的和有效的 治疗再生障碍性贫血、PNH和骨髓增生异常。 完成 PI将把大部分时间花在实验室里 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 患者在临床上，并开发新的治疗方案的基础上， 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的基因突变）赋予 PNH细胞的生存优势，使它们对 凋亡死亡，类似于其他抗凋亡癌基因。 的 这些细胞获得细胞凋亡抗性的机制 似乎是由于脂质神经酰胺的量不足。 基于他的实验室发现，表明PNH的生物学 与其他血液恶性肿瘤相似，即，抑制细胞凋亡， 他已经开始用细胞毒性化疗治疗PNH患者。 初步结果显示了显著的临床改善， 表明这种方法可以诱导完全缓解，即使是在终末期 患者 了解细胞抵抗 PIG-A突变导致的细胞凋亡将使我们更深入地了解 在PNH中观察到的克隆优势， 恶性肿瘤此外，这些临床前研究应导致 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.