Retinoids in Hematopoiesis

类维生素A在造血中的作用

• 批准号: 8464361
• 负责人: JOHN S WELCH
• 金额: $ 24.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464361
• 关键词: Acute Promyelocytic Leukemia; Binding; Biological Assay; Breeding; Cell physiology; Chimeric Proteins; Clinical; Cytotoxic Chemotherapy; Generations; Goals; Grant; Hematopoiesis; Hematopoietic; Hematopoietic Cell Growth Factors; Hemolytic Anemia; Histocompatibility Testing; In Vitro; Knowledge; Leukocytes; Ligand Binding; Ligands; Lymphoid; Mammals; Maps; Measures; Methodology; Modeling; Mus; Mutation; Myelogenous; Myeloid Progenitor Cells; Nature; Nuclear Receptors; Orphan; Pathologic; Pathway interactions; Penetrance; Pharmaceutical Preparations; Physicians; Physiological; Production; Publications; RXR; Recurrence; Regulation; Reporter; Research; Retinoid Receptor; Retinoids; Role; Scientist; Stem cells; Stimulus; System; Training; Training Support; Transcription Coactivator; Transcription Repressor/Corepressor; Vitamin A; Work; Writing; aldehyde dehydrogenases; base; career; career development; design; in vivo; leukemia; leukemogenesis; mouse model; permissiveness; programs; receptor; receptor expression; self-renewal; skills; transcription factor; tumor

Project summary This career development proposal is designed to provide training and support for the applicant to become an independent physician-scientist, who is focused on the regulation of hematopoietic self-renewal and differentiation by the retinoid receptors. The goals of this proposal are to obtain practical and didactic training in scientific methodology, technical skills, grant writing and scientific publication. Retinoids regulate the opposing pathways of hematopoietic self-renewal and differentiation. Retinoids bind to six distinct cognate retinoid receptors, altering the transcriptional activity of these nuclear receptors from transcriptional repressors to transcriptional activators. Retinoid receptors RAR¿ and RAR¿ have been implicated in programs of hematopoietic differentiation and self-renewal, respectively. In addition, acute promyelocytic leukemia is associated with the recurrent t(15;17) translocation, which creates two fusion proteins (PML-RAR¿ and RAR¿-PML), and haploinsufficiency for both RAR¿ and PML. The role of RAR¿ haploinsufficiency in early leukemic dysregulation by t(15;17) has not been defined and the distribution of natural retinoids that regulate retinoid-receptor dependent programs of self-renewal and differentiation, has not been assessed. In this project we will define the role of RAR¿ haploinsufficiency on the early dysregulation of hematopoietic self-renewal using RAR¿ deficient mice bred with our well characterized model of acute promyelocytic leukemia, the mCG-PR mouse. We will also generate a new UAS/Gal4 reporter mouse and assess the distribution of natural RAR¿, RAR¿ and RXR¿ activating retinoids across hematopoietic compartments. These studies will determine: 1). The role of RAR¿ haploinsufficiency in acute promyelocytic leukemia; 2). The spatial-temporal distribution of natural retinoid ligands during hematopoiesis; 3). Whether opposing pathways of self-renewal and differentiation are regulated by distinct receptor specific retinoids or by regulation of functional retinoid receptor availability; 4). Whether physiologic or pathologic stimuli alter hematopoiesis by regulating the production and distribution of retinoids.

项目摘要 该职业发展建议旨在为申请人提供培训和支持，以成为 独立的身体科学家，专注于造血自我更新的调节 维生素受体分化。该提议的目标是在 科学方法论，技术技能，赠款写作和科学出版物。 类视网膜类动物调节造血自我更新和分化的相对途径。视网膜类动物结合 六个不同的同源性类维生素类动物受体，改变了这些核受体的转录活性 转录受体转录激活剂。类视黄素受体rar¿ 分别在造血分化和自我更新的计划中实施。另外，急性 Promyelocytic白血病与复发t（15; 17）易位有关，该易位产生了两个融合 蛋白质（pml-rar™和rar€pml），以及RAR®和PML的单倍不足。 rar¿的角色 尚未定义t（15; 17）早期白血病失调的单倍不足，并且分布的分布 自然退休，这些退休来调节自我更新和差异化的依赖性依赖性计划，尚未 被评估。在这个项目中，我们将定义RAR¿单倍体不足对早期失调的作用 造血自我更新，使用我们急性特征模型繁殖的不足小鼠 Promyelocytic白血病，MCG-PR小鼠。我们还将生成新的UAS/GAL4报告鼠标 评估自然rar¿，rAr¿和rxr¿激活性类维生素跨造血的分布 车厢。这些研究将确定：1）。 RAR¿单倍体不足在急性临床细胞中的作用 白血病; 2）。造血期间天然类维生素性配体的时空分布； 3）。无论 自我更新和差异的相对途径受不同的接收器特定于类线素的调节，或者由 调节功能性类维生素受体的可用性； 4）。生理还是病理刺激改变 通过确定类视黄素的产生和分布来造血。