RETINOIDS IN HEMATOPOIESIS

类维生素A在造血中的作用

基本信息

批准号：
9222802
负责人：
JOHN S WELCH
金额：
$ 38.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-10 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222802
关键词：
Acute Erythroblastic Leukemia Acute Promyelocytic Leukemia Affinity Agonist Award Bexarotene Biological Assay Biology Blood Cells Bone Marrow Cells CSF3 gene Cells Clinical Clinical Trials Cutaneous Differentiation Inducer Disease Erythroid Erythroid Cells Erythroid Progenitor Cells FDA approved Fluorouracil Genes Genetic Transcription Goals Growth Hematological Disease Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Hemolytic Anemia Hexanes In complete remission Isopropanol Ligands Lipids MLL-AF9 Malignant - descriptor Mass Spectrum Analysis Methanol Molecular Mus Myelogenous Myeloid Cells Neuraminidase Pancytopenia Pathologic Patients Phenotype Physiological Plasma Play RARA gene RARB gene RARG gene RXR RXRA gene RXRB gene RXRG gene Recovery Regulation Reporter Resistance Retinoid Receptor Retinoids Retroviridae Role Signal Pathway Signal Transduction Stem cells Stress System T-Cell Lymphoma Testing Thrombocytopenia Transactivation Transcription Coactivator Transcription Repressor/Corepressor Transgenic Mice Tretinoin Undifferentiated Viral Vitamin A Work base c-myc Genes clinical application cytokine cytopenia in vivo leukemia monocyte novel phenylhydrazine physiologic stressor response self-renewal small molecule therapeutics stressor transcription factor

项目摘要

Abstract Retinoid receptors are transcription factors that play important roles regulating self-renewal and maturation of bone marrow cells, and can be changed from transcriptionally inactive states, to transcriptionally active states, by the presence of a retinoid ligand. The distribution and regulation of natural retinoid ligands is unknown. There are only two FDA approved applications for retinoid therapy in hematology (all-trans retinoic acid for acute promyelocytic leukemia, and bexarotene for cutaneous T cell lymphoma). Other attempts to integrate retinoid-based therapy into clinical hematology have been done through empiric testing, and have not been informed by a rational understanding of retinoid biology in bone marrow cells. We have developed a novel in vivo retinoid reporter assay, to determine which bone marrow cells are exposed to natural retinoids, and whether these are regulated by physiologic or pathologic stress. Unexpectedly, we have found that RXRA, but not RARA or RARG, natural retinoids are present in mouse bone marrow cells, and that these exist intracellularly in myeloid and erythroid progenitor cells, but not in stem cells. In this study, we will further define the distribution and regulation of natural retinoids in bone marrow cells in response to physiologic hematopoietic stressors (e.g. response to cytokines or recovery from cytopenias). We will determine, in which cells natural retinoids are present, and when. We will further determine whether retinoids exist intracellularly following pathologic stress (e.g. leukemia). We will determine whether natural retinoids exists in mature leukemias (monocytic and erythroleukemias) vs immature leukemias, whether this might render these forms of AML sensitive to retinoid agonists vs antagonists, and whether response could be augmented in specific forms of leukemia by inhibition of intracellular or niche-based retinoid elimination. Finally, we will identify what these natural RXR ligands are. These studies will illuminate the mechanism of retinoid sensitivity vs resistance in bone marrow cells, and will help guide the integration of retinoid therapy into clinical hematology.

抽象的性类视感受体是转录因子，起着重要作用，以调节自我更新和成熟骨髓细胞，可以从转录无活性状态变为转录活性状态，通过类维生素类药物的存在。天然类维生素性配体的分布和调节尚不清楚。在血液学中，只有两种FDA批准的类视视视感性治疗应用皮肤T细胞淋巴瘤的急性临床白血病和北沙。其他尝试集成的尝试基于视网膜类动物的临床血液疗法已通过经验性测试进行，但还没有通过对骨髓细胞中类维生素生物学的理性理解的理解。我们已经开发了一本小说体内类视黄素报道测定法，以确定哪些骨髓细胞暴露于天然类维生素类似，以及这些是由生理或病理压力调节的。出乎意料的是，我们发现了RXRA，但是不是rara或rarg，在小鼠骨髓细胞中存在天然类类动物，并且存在细胞内髓样和红细胞祖细胞，但在干细胞中没有细胞。在这项研究中，我们将进一步定义骨髓细胞中天然类维生素的分布和调节响应生理造血应激源（例如对细胞因子的反应或从细胞增多症中恢复）。我们将确定哪个细胞存在天然类维生素类似，何时。我们将进一步确定类细胞内是否存在类视黄素遵循病理应激（例如白血病）。我们将确定天然类维生素性是否成熟白血病（单核细胞和红血病）与未成熟的白血病，这是否可能导致这些形式 AML对视视视感素激动剂与拮抗剂敏感，以及是否可以以特定形式增强反应通过抑制细胞内或利基类维生素的消除来抑制白血病。最后，我们将确定这些天然RXR配体是。这些研究将阐明类视黄素灵敏度与耐药性的机制骨髓细胞，并将有助于指导性类维生素性疗法整合到临床血液学中。