THE ROLE OF ERYTHROPOIETIN RECEPTOR SIGNALING IN IRON DEFICIENCY ANEMIA

促红细胞生成素受体信号传导在缺铁性贫血中的作用

基本信息

批准号：
8680316
负责人：
GRANT C BULLOCK
金额：
$ 12.61万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-20 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680316
关键词：
Aconitate Hydratase Adverse effects Advisory Committees Affect Agonist Anemia Award Biomedical Research Bone Marrow Cell Culture Techniques Cell Differentiation process Cells Chronic Chronic Disease Citrates Clinical Commit Committee Members Core Facility Cytokine Signaling Cytoplasmic Tail Data Deficiency Diseases Development Development Plans Disease Distal Doctor of Medicine Doctor of Philosophy Enzymes Erythrocytes Erythroid Erythropoiesis Erythropoietin Erythropoietin Receptor Faculty Funding Future Goals Grant Growth Growth Factor Hematology Heme Hemoglobin Human Infusion procedures Institution Iron Iron deficiency anemia Isocitrates Isoenzymes Knockout Mice Learning Life Life Expectancy Link Longevity Mediating Mentors Metabolism Micronutrients Modeling Molecular Mus Mutant Strains Mice Mutation Myeloproliferative disease Pathology Pathway interactions Patients Polycythemia Vera Production Protein Kinase C Quality of life Receptor Signaling Recording of previous events Research Research Personnel Role STAT5A gene Scientist Serum Signal Pathway Signal Transduction Staging Testing Tissues Training Training Activity Transferrin Tyrosine Universities Virginia Work career career development clinically significant cytokine deprivation experience improved in vivo innovation instructor iron deficiency iron metabolism isocitrate medical schools meetings member mouse model mutant new therapeutic target novel therapeutics professor programs receptor research study response success tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The principle investigator, Grant Bullock, M.D., Ph.D., F.A.C.P., is a Clinical Instructor and member of the Faculty in the Department of Pathology at the University of Virginia (UVA). This K08 will support this investigator's transition to scientific independence in the field of anemia research. THE ENVIRONMENT: UVA's Pathology Department within the UVA School of Medicine is part of a large well funded biomedical research center with state-of-the-art core facilities and faculty with a history of effectively training clinician scientists. THE MENTOR: Professor Adam Goldfarb, M.D., F.A.C.P., is an ideal scientific and career mentor because he is an experienced leader in the field of molecular and cellular hematology and also is an expert practicing hematopathologist. In addition, an advisory committee of clinician scientists will meet with the candidate to provide scientific and career advice. The institution, mentor and the advisory committee members are committed to the success of the candidate. CAREER DEVELOPMENT/TRAINING ACTIVITIES: This 4- year career development plan will complete Dr. Bullock's transition to scientific independence as an academic hematopathologist. Mentoring will be more focused and formal during the first 2 years of the award and maintained at a lower intensity during the last 2 years of the award to facilitate scientific growth. A major goal of the independent research strategy described in this proposal is to obtain R01 funding during the third year. RESEARCH PLAN: Erythropoietin (Epo) is an essential cytokine for efficient red blood cell (rbc) production. Iron deficiency suppresses Epo-mediated rbc production by an unknown mechanism and causes anemia despite elevated serum Epo levels. The Epo receptor (EpoR) generates both inhibitory and stimulatory signals that suppress or promote rbc production, respectively. Iron deficiency may suppress rbc production by enforcing inhibitory signals generated by the EpoR. In this proposal we will determine the effects of iron deficiency on EpoR signaling using in vivo mouse models and physiologically relevant human cell culture models of iron deficiency anemia. Anemia affects the quality of life and the life expectancy of millions of people in the U.S. Many patients are either intolerant or unresponsive to available treatments, so alternative strategies are needed. Understanding how iron deficiency alters EpoR signaling pathways will provide new therapeutic targets for future anemia treatment strategies.

描述（由申请人提供）：首席研究员 Grant Bullock，医学博士、哲学博士、F.A.C.P.，是弗吉尼亚大学 (UVA) 病理学系的临床讲师和教员。该 K08 将支持该研究者在贫血研究领域向科学独立的过渡。环境：UVA 医学院的病理学系是一个资金雄厚的大型生物医学研究中心的一部分，该中心拥有最先进的核心设施和师资队伍，拥有有效培训临床科学家的历史。导师： Adam Goldfarb 教授，医学博士，F.A.C.P.，是一位理想的科学和职业导师，因为他是分子和细胞血液学领域经验丰富的领导者，也是一位执业血液病理学家专家。此外，由临床科学家组成的咨询委员会将与候选人会面，提供科学和职业建议。机构、导师和咨询委员会成员致力于候选人的成功。职业发展/培训活动：这项为期 4 年的职业发展计划将完成布洛克博士作为一名学术血液病理学家向科学独立的转变。在该奖项的前两年，指导将更加集中和正式，并在该奖项的最后两年保持较低的强度，以促进科学发展。本提案中描述的独立研究策略的一个主要目标是在第三年获得 R01 资助。研究计划：促红细胞生成素 (Epo) 是有效产生红细胞 (rbc) 的重要细胞因子。尽管血清 Epo 水平升高，但缺铁会通过未知机制抑制 EPO 介导的红细胞生成，并导致贫血。 Epo 受体 (EpoR) 产生抑制信号和刺激信号，分别抑制或促进红细胞生成。缺铁可能通过增强 EpoR 产生的抑制信号来抑制红细胞的产生。在本提案中，我们将使用缺铁性贫血的体内小鼠模型和生理相关的人类细胞培养模型来确定缺铁对 EpoR 信号传导的影响。贫血影响美国数百万人的生活质量和预期寿命。许多患者对现有治疗不耐受或无反应，因此需要替代策略。了解缺铁如何改变 EpoR 信号通路将为未来贫血治疗策略提供新的治疗靶点。