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: 8721196
• 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/8721196
• 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，以及一项将首席研究员Akil Merchant博士从初级教员发展为独立内科科学家的培训计划。在担任内科住院医生期间，梅钱特博士研究了正常的造血。作为约翰·霍普金斯大学威廉·松井博士实验室的肿瘤学研究员，他专注于Hedgehog(HH)途径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的癌症干细胞的研究人员，他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月被提升为助理教授。这笔赠款将支持他成为血液系统恶性肿瘤实验室转化型研究人员的目标。 Hedgehog通路是癌症治疗的一个很有前途的新靶点。以前对正常造血和白血病的研究主要集中在补丁(Ptch)和平滑(Smo)途径的上游调节因子上，并导致了相互矛盾的结论。HH途径的产量最终由三个下游Gli转录因子：Gli1、Gli2和Gli3的组合作用决定。Gli1和Gli2之间的功能冗余，Gli2和Gli3的上下文相关的激活或抑制功能，以及其他致癌信号通路对Gli因子的趋同，使我们对HH功能的理解变得复杂。Gli因子的直接抑制剂有希望作为抗癌药物，然而，需要更好地了解它们的功能，才能有效地将它们开发成治疗方法。 利用Gli1、Gli2或Gli3基因缺失的小鼠，这项拟议的研究将检查每种转录因子在正常造血和白血病中的作用。该建议的目的是：1)确定(A)Gli激活物(Gli1/Gli2)丢失和(B)Gli3丢失对正常造血的影响，2)确定(A)bcr-abl诱导的急性白血病对Gli激活物功能(Gli1/Gli2)的需求，以及(B)Flt3-ITD诱导的骨髓增殖性疾病向急性白血病的进展，3)确定(A)Gli3在白血病中是否起肿瘤抑制作用(B)Gli3的丢失使骨髓承诺的祖细胞获得自我更新(C)Gli3的表达恢复使细胞对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有更深入的了解，将有助于优化选择接受HH抑制剂治疗的患者，有助于预测H抑制剂的造血毒性，并指导可以直接针对Gli因子的设计药物。