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）：本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，以及一项旨在将主要研究者阿基勒Merchant博士从初级教员培养为独立医生-科学家的培训计划。Merchant博士在内科住院医师时研究了正常造血。作为约翰霍普金斯大学William Matsui博士实验室的医学肿瘤学研究员，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的血液学系任教，并于2011年3月晋升为助理教授。这笔赠款将支持他成为一个基于实验室的血液恶性肿瘤转化研究员的目标。 Hedgehog通路是一个很有前途的肿瘤治疗新靶点。以前在正常造血和白血病中的研究主要集中在Patched（Ptch）和Smoothened（Smo）通路的上游调节剂上，并导致了相互矛盾的结论。Hh途径的输出最终由三个下游Gli转录因子Gli 1、Gli 2和Gli 3的组合效应决定。我们对Hh功能的理解是复杂的，Gli 1和Gli 2之间的功能冗余，Gli 2和Gli 3的上下文依赖性激活或抑制功能，以及Gli因子上其他致癌信号通路的会聚。Gli因子的直接抑制剂有希望作为抗癌剂，然而，需要更好地了解它们的功能以有效地将它们开发成治疗方法。 使用Gli 1、Gli 2或Gli 3基因缺失的小鼠，拟议的研究将检查每个转录因子在正常造血和白血病中的作用。这项建议的目的是：1）确定（a）Gli激活剂的作用正常造血的（Gli 1/Gli 2）损失和（B）Gli 3损失，2）确定Gli激活剂功能的需求（a）BCR-abl诱导的急性白血病和（B）Flt 3-ITD诱导的骨髓增生性疾病向急性白血病的进展中的（Gli 1/Gli 2），3）确定（a）Gli 3在白血病中作为肿瘤抑制因子发挥作用（B）Gli 3的丧失是否赋予骨髓定向祖细胞自我更新（c）Gli 3表达的恢复是否使细胞对Smo拮抗剂敏感。研究人员假设，对单个Gli因子在癌症中的作用的更复杂的理解将有助于最佳选择Hh抑制剂治疗的患者，帮助预测H抑制剂的造血毒性，并指导可以直接靶向Gli因子的药物设计。