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 该建议描述了一项研究计划和培训计划，以促进贡多克博士的过渡 从初级教师到独立研究员。 Gondek博士研究了骨髓的遗传学 Jaroslaw博士实验室中的失败综合征，尤其是骨髓增生综合征（MDS） 克利夫兰诊所的Maciejewski。作为约翰·威廉·马苏斯博士实验室的血液学研究员 霍普金斯大学，贡德克博士研究了刺猬（HH）在开发中的作用 贡多克博士的主要导师Matsui博士是世界知名的 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 Gondek博士加入该学院，担任肿瘤学讲师，以制定研究翻译计划 MDS。 K08职业发展奖的支持将使Gondek博士能够获得其他技能， 获得心态和受保护的时间，以提高他的学术生涯。贡多克博士的目标是成为一个 MDS转化研究的独立研究者和领导者。 在此应用中，Gondek博士将研究刺猬信号的关键调节剂Gli2，在 正常造血和MD的进展。刺猬信号似乎是人类的承诺目标 恶性肿瘤及其抑制作用已显示在某些肿瘤中有效。为此，解释的努力 HH在正常和恶性造血的作用集中在途径的上游成分上（例如 修补和平滑），但结果模棱两可。在此提案中，贡多克博士将阐明 关键HH调节剂Gli2在正常和恶性造血中的功能，并将作用Gli2定义为A 选择性且安全的治疗靶标。 使用转基因动物模型，提出的研究将阐明GLI2丢失和获取的作用 正常造血和MDS进展中的功能。这些目标将通过以下来实现 目的：1）确定GLI2损失在（a）正常的确定造血和（b）使用MDS进展的作用 NUP98-HOXD13小鼠模型，2）确定（a）正常造血的GLI2激活剂的要求 及其在（b）MD的进展中的作用。 这项研究的结果将进一步了解正常和恶性的GLI2功能 造血。调查人员假设该项目将为过程提供新颖的见解 这推动了MDS的进展，并可能导致策略专注于靶向GLI2抑制作用作为一种新的治疗方法 高风险MD和白血病。