Hedgehog Signaling in the Progression of Myelodysplastic Syndromes

骨髓增生异常综合征进展中的 Hedgehog 信号转导

• 批准号: 9295429
• 负责人: Lukasz Pawel Gondek
• 金额: $ 17.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295429
• 关键词: Acceleration; Acute leukemia; Address; Age; Age-Years; Animal Model; Animals; Apoptosis; Automobile Driving; Binding; Blood; Cell Maintenance; Cell Proliferation; Cell Surface Receptors; Cells; Chronic Myeloproliferative Disorder; Clinic; Clinical Research; Clonal Hematopoietic Stem Cell; Data; Development; Diagnosis; Disease; Disease Progression; Dysmyelopoietic Syndromes; Elderly; Embryonic Development; Epigenetic Process; Erinaceidae; FLT3 gene; Faculty; Fellowship; Frequencies; Genetic; Genetic study; Goals; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic stem cells; Homeostasis; Human; Hypercellular Bone Marrow; Impairment; Individual; Inferior; Integral Membrane Protein; Investigation; K-Series Research Career Programs; Knock-out; Laboratories; Lead; Lesion; Ligands; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Mentorship; Molecular; Multiple Myeloma; Mus; Myelogenous; Oncogenic; Outcome; Output; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Process; Publishing; Recurrent disease; Regulation; Reporting; Research; Research Personnel; Role; Signal Pathway; Stem cells; Stress; Subgroup; Syndrome; Testing; Therapeutic Intervention; Time; Training Programs; Transforming Growth Factor beta; Transgenic Animals; Transgenic Mice; Translational Research; Universities; aggressive therapy; bone marrow failure syndrome; cancer stem cell; career; chromosome 5q loss; clinically significant; cytopenia; effective therapy; gain of function; high risk; improved outcome; in vivo; innovation; insight; instructor; lenalidomide; leukemia; leukemogenesis; member; mouse model; neoplastic cell; notch protein; novel; novel therapeutics; oncology; outcome forecast; overexpression; peripheral blood; prevent; programs; self-renewal; skills; smoothened signaling pathway; targeted treatment; therapeutic target; transcription factor; translational research program; tumor

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.

项目摘要 这份提案描述了一个研究计划和一个培训项目，以促进冈德克博士的过渡 从一个初级教员到一个独立调查员冈德克博士研究了骨髓的遗传学 Jaroslaw博士实验室中的失败综合征，特别是骨髓增生异常综合征（MDS） 克利夫兰诊所的马切斯基作为约翰大学威廉·松井博士实验室的血液学研究员， 霍普金斯大学的Gondek博士研究了Hedgehog（Hh）信号在发育和 血液恶性肿瘤的进展。松井博士，冈德克博士的主要导师，是一位世界知名的 他是该领域的专家，是第一个报告刺猬信号在癌症调节中的重要性的人 多发性骨髓瘤和胰腺癌中的干细胞。完成临床和研究奖学金后， 博士Gondek作为肿瘤学讲师加入了教师队伍，以制定研究转化计划， MDS来自K 08职业发展奖的支持将使贡德克博士获得额外的技能， 获得指导和受保护的时间来推进他的学术生涯。冈德克博士的目标是成为 MDS转化研究的独立研究者和领导者。 在这个应用程序中，Gondek博士将研究Hedgehog信号传导的关键调节因子Gli 2的作用， 正常造血和MDS进展。Hedgehog信号似乎是一个很有前途的靶点， 恶性肿瘤，并且其抑制已显示在某些肿瘤中有效。为此，努力解释 Hh在正常和恶性造血中的作用集中在该途径的上游组分（例如， 修补和平滑），但结果一直模棱两可。在这份提案中，冈德克博士将阐明 关键Hh调节剂Gli 2在正常和恶性造血中的功能，并将Gli 2的作用定义为 选择性和安全的治疗靶点。 使用转基因动物模型，拟议的研究将阐明Gli 2丢失和获得的作用。 在正常造血和MDS进展中的功能。这些目标将通过以下方式实现： 目的：1）使用以下方法确定Gli 2丢失在（a）正常永久性造血和（B）MDS进展中的作用： Nup 98-HoxD 13小鼠模型，2）确定Gli 2激活剂对于（a）正常造血的需求 及其在MDS的（B）进展中的作用。 本研究结果将进一步了解Gli 2在正常和恶性肿瘤中的功能 造血研究人员假设，这个项目将提供新的见解的过程， 推动MDS进展，并可能导致专注于靶向Gli 2抑制作为新治疗的策略 治疗高危骨髓增生异常综合征和白血病