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: 8906489
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906489
• 关键词: Acceleration; Activator Appliances; Acute leukemia; Antineoplastic Agents; BMI1 gene; Blood; Bone Marrow; Cell Cycle; Cell membrane; Cells; Chronic Myeloproliferative Disorder; Code; 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; 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; targeted cancer therapy; 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）：该提案描述了一项研究计划，介绍了刺猬/GLI转录因子在正常造血和白血病中的作用，以及一项培训计划，以开发主要研究员Akil Merchant博士，从初级教职员工成为独立医师科学家。商人博士研究了正常的造血症，而居民是内科。作为约翰·霍普金斯大学（Johns Hopkins University）威廉·马苏（William Matsui）实验室的医学肿瘤学研究员，他专注于刺猬（HH）途径在造血和白血病中的作用。 Matsui博士是第一位报告HH信号传导调节多发性骨髓瘤的癌症干细胞的研究者，并且是该领域公认的专家。 Merchant博士于2010年3月在Johns Hopkins的教职员工开始，并于2011年3月晋升为助理教授。该赠款将支持他成为血液系统恶性肿瘤的基于实验室的转化研究员的目标。 刺猬途径是癌症治疗的新目标。先前对正常造血和白血病的研究主要集中在修补途径（PTCH）和平滑（SMO）的上游调节剂上，并得出了矛盾的结论。 HH途径输出最终取决于三个下游GLI转录因子的组合效应：GLI1，GLI2和GLI3。 GLI1和GLI2之间的功能冗余，GLI2和GLI3的上下文依赖性激活因子或阻遏物函数以及GLI因子对其他致癌信号通路的收敛性，我们对HH功能的理解使我们对HH功能的冗余性变得复杂。直接抑制GLI因素作为抗癌剂有望更好地理解其功能，以有效地将其发展为疗法。 使用具有GLI1，GLI2或GLI3的遗传缺失的小鼠，提出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。 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）确定（a）GLI3在白血病中是否充当肿瘤抑制因子（b）GLI3的丧失赋予骨髓所承诺的祖细胞（c）恢复Gli3表达表达对SMO拮抗剂的敏感。研究人员假设对单个GLI因素在癌症中的作用的更复杂的理解将有助于最佳选择患者使用HH抑制剂治疗，有助于预测H抑制剂的造血毒性，并指导可以直接靶向GLI因子的设计药物。