The role of Hedgehog/Gli in normal hematopoiesis and leukemia

Hedgehog/Gli 在正常造血和白血病中的作用

• 批准号: 8547026
• 负责人: Akil Merchant
• 金额: $ 17.58万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547026
• 关键词: Acceleration; Activator Appliances; Acute leukemia; Antineoplastic Agents; BMI1 gene; Blood; Bone Marrow; Cell Cycle; Cell membrane; Cells; Chronic Myeloproliferative Disorder; Code; Commit; Data; Defect; Development; Disease; Disease Progression; Drug Design; Erinaceidae; FLT3 gene; Faculty; Genetic; Goals; Grant; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Individual; Internal Medicine; Laboratories; Lead; Leukemic Cell; Ligands; Lymphocyte; Lymphoid; Malignant - descriptor; Malignant Neoplasms; Marrow; Mediator of activation protein; Medical Oncology; Modeling; Multiple Myeloma; Mus; Myelogenous; Myeloproliferative disease; Oncogenic; Output; Pathway interactions; Patients; Phenotype; Physicians; Principal Investigator; Proteins; Reporting; Research; Research Personnel; Retroviridae; Role; Scientist; Signal Pathway; Stress; Tissues; Toxic effect; Training Programs; Transgenic Mice; Transplantation; Tumor Suppressor Proteins; Universities; Virus; Work; base; cancer stem cell; cancer therapy; cdc Genes; combinatorial; cyclopamine; gain of function; human SMO protein; improved; inhibitor/antagonist; insight; leukemia; leukemic stem cell; member; prevent; professor; progenitor; receptor; restoration; self-renewal; smoothened signaling pathway; transcription factor

DESCRIPTION (provided by applicant): This proposal describes a research plan into the role of the Hedgehog/Gli transcription factors in normal hematopoiesis and leukemia and a training program to develop the principal investigator, Dr. Akil Merchant, from a junior faculty member into an independent physician-scientist. Dr. Merchant studied normal hematopoiesis while a resident in internal medicine. As a medical oncology fellow in the laboratory of Dr. William Matsui, Johns Hopkins University, he focused on the role of the Hedgehog (Hh) pathway in hematopoiesis and leukemia. Dr. Matsui was the first investigator to report that Hh signaling regulates cancer stem cells in multiple myeloma and is a recognized expert in the field. Dr. Merchant started on the faculty at Johns Hopkins in March 2010 in the Department of Hematology and was promoted to Assistant Professor in March of 2011. This grant will support his goal of becoming a laboratory based translational researcher in hematologic malignancies. The Hedgehog pathway is a promising new target for cancer therapy. Previous studies in normal hematopoiesis and leukemia have focused primarily on the upstream modulators of the pathway Patched (Ptch) and Smoothened (Smo), and have led to contradictory conclusions. Hh pathway output is ultimately determined by the combinatorial effects of the three downstream Gli transcription factors: Gli1, Gli2 and Gli3. Our understanding of Hh function is complicated by functional redundancy between Gli1 and Gli2, context dependent activator or repressor functions for Gli2 and Gli3, and the convergence of other oncogenic signaling pathways on the Gli factors. Direct inhibitors of the Gli factors have promise as anticancer agents, however, a better understand of their function is needed to effectively develop them into therapies. Using mice with a genetic deletion of Gli1, Gli2, or Gli3, the proposed research will examine the roles of each transcription factor in normal hematopoiesis and leukemia. The aims of this proposal are: 1) Determine the effect of (a) Gli activator (Gli1/Gli2) loss and (b) Gli3 loss on normal hematopoiesis, 2) Determine the requirement for Gli activator function (Gli1/Gli2) in (a) BCR-abl induced acute leukemia and (b) the progression of Flt3-ITD induced myeloproliferative disease to acute leukemia, 3) Determine if (a) Gli3 functions as a tumor suppressor in leukemia (b) loss of Gli3 confers self-renewal to bone marrow committed progenitors (c) restoration of Gli3 expression sensitizes cells to Smo antagonists. The investigators hypothesize that a more sophisticated understanding of the role of individual Gli factors in cancer will aid in optimally selecting patients for treatment with Hh inhibitors, help predict the hematopoietic toxicities of H inhibitors, and guide the design drugs that can directly target the Gli factors.

描述（由申请人提供）：该提案描述了一项关于 Hedgehog/Gli 转录因子在正常造血和白血病中的作用的研究计划，以及一项旨在将首席研究员 Akil Merchant 博士从初级教员培养成独立医师科学家的培训计划。 Merchant 医生在内科住院医师期间研究了正常造血功能。作为约翰·霍普金斯大学 William Matsui 博士实验室的肿瘤内科研究员，他专注于 Hedgehog (Hh) 通路在造血和白血病中的作用。松井博士是第一个报告 Hh 信号调节多发性骨髓瘤中癌症干细胞的研究者，是该领域公认的专家。 Merchant 博士于 2010 年 3 月开始在约翰霍普金斯大学血液学系任教，并于 2011 年 3 月晋升为助理教授。这笔赠款将支持他成为血液恶性肿瘤实验室转化研究员的目标。 Hedgehog 通路是癌症治疗的一个有前景的新靶点。以往对正常造血和白血病的研究主要集中在Patched (Ptch) 和Smoothened (Smo) 通路的上游调节剂上，并得出了相互矛盾的结论。 Hh 通路的输出最终由三个下游 Gli 转录因子：Gli1、Gli2 和 Gli3 的组合效应决定。我们对 Hh 功能的理解因 Gli1 和 Gli2 之间的功能冗余、Gli2 和 Gli3 的上下文依赖性激活子或抑制子功能以及 Gli 因子上其他致癌信号通路的融合而变得复杂。 Gli 因子的直接抑制剂有望成为抗癌药物，然而，需要更好地了解其功能才能有效地将其开发为疗法。 拟议的研究将使用 Gli1、Gli2 或 Gli3 基因缺失的小鼠来检查每种转录因子在正常造血和白血病中的作用。该提案的目的是：1) 确定 (a) Gli 激活剂 (Gli1/Gli2) 丢失和 (b) Gli3 丢失对正常造血的影响，2) 确定 (a) BCR-abl 诱导的急性白血病和 (b) Flt3-ITD 诱导的骨髓增生性疾病进展为急性白血病中对 Gli 激活剂功能 (Gli1/Gli2) 的需求， 3) 确定 (a) Gli3 是否在白血病中充当肿瘤抑制因子 (b) Gli3 的缺失赋予骨髓定向祖细胞自我更新 (c) Gli3 表达的恢复使细胞对 Smo 拮抗剂敏感。研究人员推测，更深入地了解单个 Gli 因子在癌症中的作用将有助于最佳选择接受 Hh 抑制剂治疗的患者，帮助预测 H 抑制剂的造血毒性，并指导设计可直接靶向 Gli 因子的药物。