Hedgehog Signaling in the Progression of Myelodysplastic Syndromes

项目摘要 该提案描述了一项研究计划和一项培训计划，以促进冈德克博士的过渡 从初级教员到独立调查员。冈德克博士研究了骨髓的遗传学 雅罗斯瓦夫博士实验室的衰竭综合征，特别是骨髓增生异常综合征(MDS) 克利夫兰诊所的马基耶斯基。作为约翰斯医院威廉·松井博士实验室的血液学研究员 霍普金斯大学的冈德克博士研究了Hedgehog(HH)信号在发育和发育中的作用。 恶性血液病的进展。冈德克博士的主要导师松井博士是一位享誉世界的 他是该领域的专家，第一个报道了Hedgehog信号在癌症调控中的重要性 多发性骨髓瘤和胰腺癌中的干细胞。在完成临床和研究奖学金后 冈德克博士以肿瘤学讲师的身份加入教职，开发研究翻译计划 MDS。K08职业发展奖的支持将使冈德克博士获得额外的技能， 接受导师和受保护的时间，以推进他的学术生涯。冈德克博士的目标是成为一名 MDS翻译研究的独立调查者和领导者。 在这项应用中，冈德克博士将研究Hedgehog信号的关键调节因子Gli2在 正常的造血和MDS的进展。刺猬信号似乎是人类的一个很有希望的靶点 恶性肿瘤及其抑制已被证明对某些肿瘤有效。为此，我们努力解释 HH在正常和恶性造血中的作用主要集中在该途径的上游成分(如： 修补和平滑)，但结果一直含糊其辞。在这份提案中，冈德克博士将阐明 关键的HH调节因子Gli2在正常和恶性造血中的作用并将其定义为 选择安全的治疗靶点。 利用转基因动物模型，这项拟议的研究将阐明Gli2丢失和Gli2获得的作用。 在正常造血和MDS进展中的作用。这些目标将通过以下方式实现 目的：1)确定Gli2丢失在(A)正常的最终造血和(B)MDS进展中的作用 Nup98-HoxD13小鼠模型，2)确定Gli2激活剂对(A)正常造血的需求 以及它在(B)MDS进展中的作用。 本研究结果将为进一步了解Gli2在正常和恶性病变中的功能奠定基础 造血术。调查人员假设，这个项目将为这些过程提供新的见解 这推动了MDS的进展，并可能导致将靶向Gli2抑制作为一种新的治疗方法的策略 用于高危MDS和白血病。

Project Abstract This proposal describes a research plan and a training program to facilitate Dr. Gondek’s transition from a junior faculty member to an independent investigator. Dr. Gondek studied the genetics of Bone Marrow Failure Syndromes and in particular Myelodysplastic Syndromes (MDS) in the laboratory of Dr. Jaroslaw Maciejewski at Cleveland Clinic. As a hematology fellow in the laboratory of Dr. William Matsui at The Johns Hopkins University, Dr. Gondek studied the role of Hedgehog (Hh) signaling in the development and progression of hematologic malignancies. Dr. Matsui, Dr. Gondek’s primary mentor, is a world-renowned expert in the field and was the first to report the importance Hedgehog signaling in the regulation of cancer stem cells in multiple myeloma and pancreatic cancer. Upon completion of his clinical and research fellowship Dr. Gondek joined the faculty as an Instructor of Oncology to develop the research translational program in MDS. Support from the K08 Career Development Award will enable Dr. Gondek to gain additional skills, receive mentorship and protected time to advance his academic career. Dr. Gondek’s goal is to become an independent investigator in and leader in MDS translational research. In this application Dr. Gondek will study the role of a key regulator of Hedgehog signaling, Gli2, in normal hematopoiesis and progression of MDS. Hedgehog signaling seems to be a promising target in human malignancies and its inhibition has shown to be effective in certain tumors. To this end, the efforts to explain the role of Hh in normal and malignant hematopoiesis focused on upstream components of the pathway (e.g. Patched and Smoothened) but the results have been ambiguous. In this proposal Dr. Gondek will elucidate the function of the key Hh regulator Gli2 in normal and malignant hematopoiesis and define the role Gli2 as a selective and safe therapeutic target. Using transgenic animal models the proposed research will elucidate the role of Gli2 loss and gain-of- function in normal hematopoiesis and MDS progression. These goals will be achieved through the following aims: 1) Determine the role of Gli2 loss in (a) normal definitive hematopoiesis and (b) MDS progression using Nup98-HoxD13 mouse model, 2) Determine the requirements of Gli2 activator for (a) normal hematopoiesis and its role in (b) progression of MDS. Results of this research will further the understanding of Gli2 function in normal and malignant hematopoiesis. The investigators hypothesize that this project will provide novel insights into the processes that drive MDS progression and may lead to strategies focused on targeted Gli2 inhibition as a new treatment for high risk MDS and leukemia.