Cellular Signaling Pathways in the Regulation of Fetal Hemoglobin for Treatment of Sickle Cell Disease

调节胎儿血红蛋白治疗镰状细胞病的细胞信号通路

• 批准号: 10592428
• 负责人: Scott Alan Peslak
• 金额: $ 16.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592428
• 关键词: Adult; Animal Model; Auxins; Avascular necrosis of bone; Award; Bioinformatics; Blood; CRISPR/Cas technology; Cell Culture Techniques; Cell Line; Cells; Cellular biology; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Development; Dissection; Drug Targeting; Engineering; Erythrocytes; Erythroid; Erythroid Cells; Fellowship; Fetal Hemoglobin; Funding; Future; GCN2 protein kinase; Gene Expression Regulation; Global Change; Goals; Hematology; Heme; Hemoglobin; Hemoglobin concentration result; Hemoglobinopathies; Human; Individual; Internal Medicine; International; Kidney Diseases; Knowledge; Mass Spectrum Analysis; Mediating; Mentors; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; Oncology; Outcome Study; Pathway interactions; Patients; Pediatric Hospitals; Pennsylvania; Persons; Pharmaceutical Preparations; Phenotype; Philadelphia; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physicians; Production; Protein Kinase; Protein Kinase Interaction; Protein phosphatase; Proteome; Regulation; Regulatory Pathway; Research; Research Personnel; Residencies; Resources; Role; Sampling; Scholars Program; Scientist; Sickle Cell; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Stroke; Surveys; System; Techniques; Testing; Therapeutic; Training; Transplantation; Universities; Up-Regulation; Vocational Guidance; Xenograft procedure; acute chest syndrome; beta Thalassemia; career; career development; combinatorial; experience; functional genomics; genetic regulatory protein; genome editing; improved; in vivo; in vivo Model; inhibitor; insight; instructor; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; phosphoproteomics; research and development; sickling; skills; small molecule; synergism; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The goal of the proposed five-year training plan is the development of my independent research career as an academic adult hematology physician-scientist studying red cell biology and hemoglobin regulation. I have completed internal medicine residency and hematology/oncology fellowship training at the University of Pennsylvania, and I am currently a Senior Fellow/Program Scholar who will transition in July 2021 to an Instructor and attending physician in the Division of Hematology/Oncology at UPenn. I am specifically seeking to develop and refine the skills that will be required for a successful career as an independent investigator, including expertise in gene regulation, signaling pathways, functional genomics, and bioinformatics. My overarching goal is to improve therapeutic approaches for sickle cell disease (SCD) via study of key signaling pathways that regulate expression of the fetal form of hemoglobin. My mentor for this award is Dr. Gerd Blobel, an internationally recognized leader in erythroid gene regulation and hemoglobin switching. To add depth and breadth to my scientific and career guidance, I have assembled a Mentoring Committee composed of physician-scientists from diverse and complementary fields. I will have the full resources of UPenn and the Children’s Hospital of Philadelphia available for the completion of my research and career development goals. The goal of this proposal is to elucidate the molecular mechanisms of PP6C, a novel regulator of fetal hemoglobin, to improve upon current treatments for SCD and beta-thalassemia. SCD afflicts millions of people worldwide and can lead to severe complications including acute chest syndrome, stroke, avascular necrosis of bone, and nephropathy. Although increasing levels of fetal hemoglobin (HbF) significantly reduces cell sickling and SCD-related morbidity and mortality, effective HbF pharmacologic induction has been an elusive goal. To this end, I recently carried out a CRISPR-Cas9 based screen to identify additional potentially druggable molecules to increase HbF production; this screen uncovered the protein phosphatase PP6C as a novel HbF regulator. This proposal will explore PP6C-regulated pathways with both hypothesis-driven and unbiased approaches and will investigate suitability of PP6C as a target for HbF induction. These objectives will be achieved via three Specific Aims: to elucidate key mechanistic pathways in the regulation of HbF by PP6C, to explore potential cooperativities of PP6C with other HbF regulatory pathways utilizing CRISPR-Cas12a-based techniques; and to test the role of PP6C-mediated HbF regulation in SCD and in vivo models. The outcome of these studies will deepen our understanding of signaling pathways that govern HbF expression and unveil new therapeutic opportunities in SCD. Completion of these aims will consolidate my experience in models of hemoglobin switching, further my training in bioinformatics and functional genomics, and provide the basis for a future R01 funding proposal. These studies will leave me uniquely prepared for an independent career as a physician-scientist with a focus on red cell biology and hemoglobinopathies.

项目总结/摘要 拟议的五年培训计划的目标是发展我的独立研究生涯， 一个学术成人血液学医生，科学家研究红细胞生物学和血红蛋白调节。我有 完成内科住院医师和血液学/肿瘤学奖学金培训，在大学 宾夕法尼亚州，我目前是一名高级研究员/项目学者，将于2021年7月过渡到 宾夕法尼亚大学血液学/肿瘤学系讲师和主治医师。我特别寻求 发展和完善作为独立调查员成功职业所需的技能， 包括基因调控、信号通路、功能基因组学和生物信息学方面的专业知识。我 总体目标是通过研究关键信号通路来改善镰状细胞病（SCD）的治疗方法。 调节胎儿形式血红蛋白表达的途径。我的导师是Gerd Blobel博士 国际公认的红细胞基因调控和血红蛋白转换的领导者。为了增加深度和 为了拓宽我的科学和职业指导，我组建了一个指导委员会， 来自不同和互补领域的医学科学家。我将拥有宾州大学的全部资源 可供费城儿童医院完成我的科研和职业发展目标. 本研究的目的是阐明PP 6C的分子机制，PP 6C是一种新的胎儿生长调节因子， 血红蛋白，以改善目前对SCD和β-地中海贫血的治疗。SCD困扰着数百万人 并可导致严重并发症，包括急性胸部综合征，中风，缺血性坏死， 骨和肾病。尽管胎儿血红蛋白（HbF）水平的增加显著减少了细胞镰状化， 和SCD相关的发病率和死亡率，有效的HbF药理学诱导一直是一个难以捉摸的目标。到 为此，我最近进行了一项基于CRISPR-Cas9的筛选，以确定其他潜在的药物 分子来增加HbF的产生;该筛选发现蛋白磷酸酶PP 6C是一种新的HbF 调节器该提案将探索PP 6C调控的途径，既有假设驱动，又无偏见 方法，并将研究PP 6C作为HbF诱导靶点的适用性。这些目标将 通过三个具体目标实现：阐明PP 6C调节HbF的关键机制途径， 利用基于CRISPR-Cas 12 a的研究，探索PP 6C与其他HbF调控途径的潜在合作性。 技术;并测试PP 6C介导的HbF调节在SCD和体内模型中的作用。的结果 这些研究将加深我们对控制HbF表达的信号通路的理解，并揭示新的 SCD的治疗机会。这些目标的完成将巩固我在模型方面的经验， 血红蛋白转换，进一步我在生物信息学和功能基因组学的培训，并提供基础， 未来R 01融资提案。这些研究将使我为独立的职业生涯做好独特的准备， 他是一位专注于红细胞生物学和血红蛋白病的医生兼科学家。