Control of Telomere Homeostasis by Nucleotide Metabolism in Hematopoiesis

造血过程中核苷酸代谢对端粒稳态的控制

基本信息

批准号：
10606171
负责人：
William Mannherz
金额：
$ 4万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606171
关键词：
Academic skills Age Aplastic Anemia Award Biochemical Bioinformatics Biology Blood Cells Bone Marrow Transplantation Bone marrow failure Boston CRISPR screen Cell division Cells Childhood Chromosomes Communication DNA Data Defect Degenerative Disorder Deoxyribonucleotides Diagnosis Disease Dyskeratosis Congenita Dysmyelopoietic Syndromes Environment Face Future Genes Genetic Genetic Screening Genetic study Genome Stability Goals Growth Health Hematology Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis Human Human Cell Line Human Genetics Human Genome In Vitro Inherited Intervention Investigation Knowledge Laboratories Length Life Link Liver Cirrhosis Mentors Metabolism Modeling Mutation Nucleotides Organ Transplantation Organ failure Outcome Output Pathway interactions Patients Pediatric Hospitals Physicians Physiological Population Predisposition Prevalence Prognosis Pulmonary Fibrosis RNA-Directed DNA Polymerase Regenerative capacity Regulation Research Risk Role Scientist Somatic Mutation Supplementation Supportive care Systemic Therapy Systemic disease TERT gene Telomerase Telomere Maintenance Telomere Maintenance Gene Telomere Shortening Testing Therapeutic Thymidine Training Programs Translating Translations Transplant Recipients Work bone marrow failure syndrome career career preparation design experience experimental study genome wide association study genome wide screen genome-wide human model human population genetics improved in vivo in vivo Model induced pluripotent stem cell loss of function medical schools metabolomics mutant novel novel strategies nucleotide metabolism prevent promoter protein structure regenerative tissue senescence small molecule telomere

Academic skills Age Aplastic Anemia Award Biochemical Bioinformatics Biology Blood Cells Bone Marrow Transplantation Bone marrow failure Boston CRISPR screen Cell division Cells Childhood Chromosomes Communication DNA Data Defect Degenerative Disorder Deoxyribonucleotides Diagnosis Disease Dyskeratosis Congenita Dysmyelopoietic Syndromes Environment Face Future Genes Genetic Genetic Screening Genetic study Genome Stability Goals Growth Health Hematology Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis Human Human Cell Line Human Genetics Human Genome In Vitro Inherited Intervention Investigation Knowledge Laboratories Length Life Link Liver Cirrhosis Mentors Metabolism Modeling Mutation Nucleotides Organ Transplantation Organ failure Outcome Output Pathway interactions Patients Pediatric Hospitals Physicians Physiological Population Predisposition Prevalence Prognosis Pulmonary Fibrosis RNA-Directed DNA Polymerase Regenerative capacity Regulation Research Risk Role Scientist Somatic Mutation Supplementation Supportive care Systemic Therapy Systemic disease TERT gene Telomerase Telomere Maintenance Telomere Maintenance Gene Telomere Shortening Testing Therapeutic Thymidine Training Programs Translating Translations Transplant Recipients Work bone marrow failure syndrome career career preparation design experience experimental study genome wide association study genome wide screen genome-wide human model human population genetics improved in vivo in vivo Model induced pluripotent stem cell loss of function medical schools metabolomics mutant novel novel strategies nucleotide metabolism prevent promoter protein structure regenerative tissue senescence small molecule telomere

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项目摘要

PROJECT SUMMARY/ABSTRACT: Telomere homeostasis is critical for cellular replicative capacity and human health. Telomeres shorten with cellular replication and when critically short, trigger senescence and halt cell division. Inherited mutations in telomere maintenance genes are associated with severe hematopoietic disorders including childhood-onset bone marrow failure, aplastic anemia, and myelodysplastic syndrome, as well as non-hematopoietic conditions including liver cirrhosis and pulmonary fibrosis. These diseases are collectively referred to as telomere biology disorders (TBDs). Treatment for TBDs is centered on supportive care and bone marrow or organ transplant which often have poor outcomes and leave patients at risk for other disease manifestations. New approaches to therapeutically lengthen telomeres and treat TBDs are needed. In order to identify novel pathways controlling human telomere length, we recently performed a genome-wide CRISPR/Cas9 screen with a telomere length readout. In addition to identifying known telomere maintenance genes, we identified an association between several nucleotide metabolism genes and telomere length. Recent human genome wide association studies have also connected nucleotide metabolism genes and telomere length in blood cells. Preliminary experiments performed in our laboratory demonstrate that both genetic and small molecule perturbations of nucleotide metabolism can rapidly and robustly alter telomere length in human cells, including induced pluripotent stem cells derived from patients with TBDs. However, there are fundamental knowledge gaps both in the mechanisms underlying this effect, and whether manipulating nucleotide metabolism could alter telomere maintenance in the hematopoietic system, which could be therapeutically useful. Here, we aim to uncover how nucleotide metabolism perturbations alter telomere length in human cells, including in vitro and in vivo models of human hematopoiesis. This study consists of two aims to investigate: (1) how altering nucleotide metabolism genes impacts telomere maintenance, and (2) how small molecule manipulation of nucleotide metabolism alters telomere homeostasis, in human cells including primary hematopoietic stem and progenitor cells. For this F30 award, the PI has designed a research strategy and training program that will provide him with: (1) fundamental expertise in metabolomics, bioinformatics, and telomere biology, (2) an expert group of mentors and collaborators to promote not only research expertise, but also career-long academic skills including grantsmanship and scientific communication, and (3) experience performing translation-focused hematology research in preparation for his career goal as a physician-scientist. This proposal will take place in the rich and collaborative Harvard Medical School and Boston Children’s Hospital research environments. Completion of this work is expected to establish nucleotide metabolism as a critical regulator of human telomere homeostasis, with therapeutic implications for the treatment of hematopoietic diseases with high unmet need including bone marrow failure and aplastic anemia, as well as other non-hematopoietic degenerative diseases.

项目摘要/摘要：端粒稳态对于细胞复制能力和人类健康至关重要。端粒缩短细胞复制，并且在严重短暂时，触发感应和停止细胞分裂。继承突变端粒维持基因与包括儿童期在内的严重造血疾病有关骨髓衰竭，增生性贫血和骨髓增生综合征以及非脊髓性疾病包括肝硬化和肺纤维化。这些疾病统称为端粒生物学疾病（TBD）。 TBD的治疗以支撑性护理和骨髓为中心或组织移植通常的结果差，使患者有其他疾病表现的风险。新方法需要治疗长度的端粒和治疗TBD。为了识别控制的新途径人类端粒长度，我们最近进行了全基因组CRISPR/CAS9屏幕，带有端粒长度读出。除了确定已知的端粒维护基因外，我们还确定了几个核基因组基因和端粒长度。最近的人类基因组关联研究还连接了血细胞中的核苷酸代谢基因和端粒长度。初步实验在我们的实验室中进行的表明，核苷酸的遗传和小分子扰动代谢可以快速，稳健地改变人类细胞中的端粒长度，包括诱导的多能茎源自TBD的患者的细胞。但是，机制的基本知识差距这种效果的基础，以及操纵核苷酸代谢是否可以改变端粒的维持造血系统，这可能是有用的。在这里，我们旨在发现核苷酸如何代谢扰动改变了人类细胞中的端粒长度，包括人体的体外模型造血。这项研究包括两个旨在研究的目的：（1）如何改变核丁基代谢基因影响端粒维持，以及（2）核苷酸代谢的小分子操作如何改变端粒稳态，包括原发性造血干和祖细胞在内的人类细胞中。对于此F30 奖项，PI设计了一项研究策略和培训计划，该计划将为他提供：（1）基本代谢组学，生物信息学和端粒生物学专家（2）合作者不仅促进研究专业知识，还促进职业生涯长期的学术技能授予技巧和科学沟通，以及（3）表演以翻译为中心的血液学的经验研究他作为身体科学家的职业目标的研究。该建议将在富人和哈佛大学协作和波士顿儿童医院的研究环境。完成此操作预计工作将建立核苷酸代谢作为人类端粒体内平衡的关键调节剂，并与治疗高未满足需要的造血疾病（包括骨髓）的治疗意义衰竭和性贫血以及其他非脊髓性退行性疾病。