Elucidation of Novel Anti-apoptotic Pathways in Erythropoiesis

红细胞生成中新的抗凋亡途径的阐明

• 批准号: 8397661
• 负责人: Yongping Wang
• 金额: $ 14.85万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-19 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397661
• 关键词: 1-Phosphatidylinositol 3-Kinase; Anemia; Apoptosis; Apoptosis Promoter; Apoptotic; Back; Binding; Bioinformatics; Caliber; Candidate Disease Gene; Cell Differentiation process; Cell Line; Cell Proliferation; Cell Survival; Cells; Chronic Kidney Failure; Clinical; Clinical Pathology; Clinical Skills; Complement; Complementary DNA; Complication; Consensus Sequence; Development; Differentiation and Growth; Dissection; Environment; Erythrocytes; Erythropoiesis; Erythropoietin; Estrogen Receptors; Family; Fellowship; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Health; Hematopathology; Hematopoietic; Interleukin-3; International; Janus kinase; K-Series Research Career Programs; Knowledge; Libraries; Medicine; Mentors; Mentorship; Methodology; Microarray Analysis; Mus; Mutagenesis; Pathway interactions; Pattern; Pennsylvania; Phosphorylation; Phosphotransferases; Physicians; Play; Process; Program Development; Pronormoblasts; Public Health; RNA; RNA Interference; RNA library; Receptor Activation; Receptor Cell; Regulation; Research; Residencies; Resources; Role; STAT protein; Scientist; Signal Pathway; Signal Transduction; Small RNA; System; Testing; Therapeutic; Training; Training Programs; Transfusion; Transgenes; Tumor Necrosis Factor-alpha; Universities; Withdrawal; authority; base; career; cost; design; embryonic stem cell; human GATA1 protein; improved; interest; novel; protein complex; screening; skills; tool; transcription factor; tumor

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in Transfusion Medicine. The PI has completed his Clinical Pathology residency and Transfusion Medicine Fellowship at the University of Pennsylvania (UPenn), and is developing both his clinical skills and his research career by studying erythropoietic differentiation using a novel short hairpin-loop RNA (shRNA) library. UPenn provides an ideal training environment by providing both intellectual and physical resources of the highest caliber, backed by a strong track record of winning career development awards. The PI will conduct his research under the mentorships of Dr. Robert B. Wilson, an internationally renowned geneticist, and Dr. Mitchell Weiss, an international authority on erythropoiesis. The PI will be advised by a committee of highly regarded scientists, including Drs. Donald Baldwin (Director of the UPenn Microarray Core), Zissimos Mourelatos (an expert on RNA interference), Mariusz Wasik (Director of Hematopathology), and Isidore Rigoutsos (Manager of IBM Bioinformatics). In addition, Dr. Donald Siegel, Vice-chair of Transfusion Medicine, will mentor the PI's clinical development. The proposed research exploits the recent discovery of RNA interference (RNAi), an important mechanism of genetic regulation. Unlike existing RNAi libraries, which have significant sequence bias and are expensive to make, the novel shRNA library constructed by the PI is unbiased and can be made at a fraction of the cost. The PI has identified shRNAs from the random library that confer protection from IL3-withdrawal-induced apoptosis, improved one of the hits through random mutagenesis, and shown that different hit shRNAs differentially alter gene expression patterns by microarray analysis. The PI will apply similar methodologies to further improve his hits and discover the specific gene sets altered by these shRNAs. He will also study the pathways modulated by his shRNAs during erythropoietic differentiation, either alone or in cooperation with erythropoietin signaling. Finally, he will use his library to discover novel shRNAs that can induce erythropoiesis themselves, and elucidate their mechanisms of action. The strength of this proposal is the use of a unique, random shRNA library to influence erythropoiesis in an agnostic approach, with obvious translational and therapeutic implications. Anemia is a major complication in chronic renal disease, and is the most common indication for transfusion. Therefore, the understanding and potential influence of erythropoiesis is particularly relevant to public health and the PI's said clinical interest. In the near term, the PI will focus on acquiring knowledge and developing his research skills in erythropoiesis, RNAi and bioinformatics. In the long run, the PI's career objective is to become an independent physician-scientist with roughly one quarter of his effort devoted to transfusion medicine and other three quarters to research on erythropoiesis.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，以开发输血医学的学术生涯。 PI在宾夕法尼亚大学（UPENN）完成了他的临床病理居住和输血医学研究金，并通过使用新型的短发夹 - 环RNA（SHRNA）图书馆来研究促红细胞生成差异，从而发展了他的临床技能和研究生涯。 Upenn通过提供最高能力的智力和物理资源，提供理想的培训环境，并获得赢得职业发展奖的良好记录。 PI将根据国际知名的遗传学家Robert B. Wilson博士和erythropoiesis的国际权威米切尔·魏斯（Mitchell Weiss）博士进行研究。 PI将由包括Drs在内的备受推崇的科学家的委员会建议。唐纳德·鲍德温（Upenn Microarre Core的主任），Zissimos Mourelatos（RNA干扰的专家），Mariusz Wasik（造血病理学的总监）和Isidore Rigoutsos（IBM BioInformatics的经理）。此外，输血医学副主席Donald Siegel博士将指导PI的临床发展。 拟议的研究利用了最近发现RNA干扰（RNAI），这是遗传调节的重要机制。与现有的RNAi库（具有明显的序列偏差且制造昂贵的RNAi库不同，由PI构建的新型shrna库是公正的，可以以成本的一小部分制作。 PI从随机文库中鉴定出shRNA，这些shRNA允许脱离IL3-WithDrawal诱导的细胞凋亡，通过随机诱变改善了其中一种命中，并表明不同的命中SHRNA通过微阵列分析对基因表达模式进行了差异化。 PI将采用类似的方法来进一步改善他的命中，并发现这些shRNA改变的特定基因集。他还将研究他的shRNA在红细胞生成分化过程中调节的途径，无论是单独还是与促红细胞生成素信号传导合作。最后，他将利用自己的图书馆发现可以诱导红细胞生成的新颖shrnas，并阐明其作用机理。该提议的优势在于使用独特的随机shRNA文库在不可知论的方法中影响红细胞生成，具有明显的翻译和治疗意义。 贫血是慢性肾脏疾病的主要并发症，是输血的最常见指示。因此，促红细胞生成的理解和潜在影响与公共卫生和PI所述临床兴趣特别相关。在短期内，PI将着重于获取知识并发展他在红血病，RNAi和生物信息学方面的研究技能。从长远来看，PI的职业目标是成为一名独立的医师科学家，大约四分之一的努力致力于输血医学和其他四分之三以研究红细胞生成。