The Glucocorticoid Receptor as Signal Integrator: Studying All Drug Resistance

糖皮质激素受体作为信号积分器：研究所有耐药性

• 批准号: 8299116
• 负责人: MILES A PUFALL
• 金额: $ 23.97万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299116
• 关键词: Acute Lymphocytic Leukemia; Adverse effects; Allosteric Regulation; Apoptosis; Apoptotic; Asthma; Autoimmune Diseases; Award; B-Cell Acute Lymphoblastic Leukemia; Binding Sites; Biochemical; Biology; Calorimetry; Cell Line; Cells; ChIP-seq; Characteristics; Childhood; Chromatin; Communication; Complex; Computing Methodologies; Cues; DNA; DNA Binding; DNA Binding Domain; DNA Sequence; Data Set; Development; Diabetes Mellitus; Disease; Drug resistance; Drug usage; Face; Future; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Glucocorticoid Receptor; Glucocorticoid-induced apoptosis; Glucocorticoids; Goals; Health; Hematopoietic; Histone H3; Hormones; Hypertension; In Vitro; Intervention; Learning; Lysine; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Messenger RNA; Methods; Modeling; Modification; Nuclear Extract; Nuclear Magnetic Resonance; Organ Transplantation; Osteoporosis; Outcome; Output; Pharmaceutical Preparations; Pre-B Acute Lymphoblastic Leukemia; Prednisone; Property; Proteins; RNA; Reading; Resistance; Resources; Response Elements; Screening procedure; Signal Pathway; Signal Transduction; Specific qualifier value; Structural Models; System; Testing; Thermodynamics; Time; Tissues; Training; Translating; Work; abstracting; base; career development; cell type; effective therapy; experience; genome-wide; glucocorticoid-induced orphan receptor; hormone resistance; human tissue; outcome forecast; programs; receptor; receptor binding; receptor function; response; transcription factor

Project Summary/Abstract Proteins lie at the nodes of signaling pathways, and it is their task to integrate these signals to direct a specific output - one that is tailored to the needs of the cell at the time. Dr. Miles Pufall has studied signal integration using the glucocorticoid receptor (GR), in particular the mechanistic basis of allosteric regulation by DNA sequence. This K99/R00 award will provide him with the resources, time, and training to develop systems that translate the structural and biophysical basis of GR allosteric integration into an understanding of the signaling aberrations that result in childhood pre-B acute lymphoblastic leukemia (B-ALL) treatment resistance. This work will enable development of selective interventions that direct allosteric networks in the protein. This award will allow Dr. Pufall to achieve the following career development goals: 1) Develop a grounding in hematopoietic development and disease; 2) Learn to work with primary tissue; 3) Gain experience with genomic data sets to develop future studies; and 4) Develop an in vitro system to test signal integration principles. The glucocorticoid receptor orchestrates a program of gene expression in response to cellular signals by nucleating the assembly of regulatory complexes at specific DNA response elements throughout the genome. In B-ALL, synthetic glucocorticoids directed against GR are an effective treatment, which in combination with other drugs, work to induce an apoptotic program. However those who do not respond to glucocorticoids face a grim prognosis. Dr. Pufall hypothesizes that signaling pathways that allosterically regulate GR have been disrupted, changing the normal function of the receptor, and blocking apoptosis. He will test this hypothesis in three aims: 1) Identify changes in glucocorticoid induced gene expression programs, GR binding, and marks for active chromatin in glucocorticoid sensitive and resistant acute lymphoblastic leukemia; 2) Purify GR regulatory complexes from select response elements and identify components; and 3) Identify allosteric wires emanating from the DNA binding domain of GR, and determine how signals impinge on these wires.

项目摘要/摘要 蛋白质位于信号通路的节点上，他们的任务是集成这些信号以指导特定 输出 - 当时根据单元格的需求量身定制的输出。 Miles Pufall博士研究了信号集成 使用糖皮质激素受体（GR），尤其是DNA变构调节的机械基础 顺序。该K99/R00奖将为他提供开发系统的资源，时间和培训 将GR变构整合的结构和生物物理基础转化为对 导致儿童期前急性淋巴细胞白血病（B-ALL）治疗的信号畸变 反抗。这项工作将使选择性干预措施开发，以指导在 蛋白质。该奖项将使Pufall博士能够实现以下职业发展目标：1） 基础造血发育和疾病； 2）学会与原始组织一起工作； 3）增益 具有基因组数据集的经验，以开发未来的研究； 4）开发一个体外系统来测试信号 集成原则。 糖皮质激素受体根据响应细胞信号来协调基因表达程序 在整个基因组的特定DNA响应元件上的调节复合物组装成核。 在B-All中，针对GR的合成​​糖皮质激素是一种有效的治疗方法 其他药物，诱导凋亡计划的努力。但是那些对糖皮质激素不反应的人 面对严峻的预后。 Pufall博士假设，构摩斯调节GR的信号传导途径 被破坏，改变受体的正常功能并阻止凋亡。他会测试这个 三个目标中的假设：1）确定糖皮质激素诱导的基因表达程序的变化，GR结合， 和糖皮质激素敏感和抗性急性淋巴细胞白血病中活性染色质的标记； 2） 从某些响应元素中纯化GR调节复合物并识别组件； 3）识别 从GR的DNA结合结构域发出的变构线，并确定信号如何影响这些域 电线。