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

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.

项目概要/摘要：端粒稳态对于细胞复制能力和人类健康至关重要。细胞复制，当非常短时，会引发衰老并停止细胞分裂的遗传突变。端粒维持基因与严重造血疾病（包括儿童期发病）有关骨髓衰竭、再生障碍性贫血、骨髓增生异常综合征以及非造血疾病包括肝硬化和肺纤维化这些疾病统称为端粒生物学。 TBD 的治疗以支持治疗和骨髓或器官移植为中心。这通常会产生不良结果，并使患者面临其他疾病表现的风险。为了确定新的控制途径，需要进行治疗性延长端粒并治疗 TBD。人类端粒长度，我们最近进行了全基因组 CRISPR/Cas9 筛选，确定了端粒长度除了识别已知的端粒维持基因之外，我们还确定了两者之间的关联。一些核苷酸代谢基因和端粒长度的最新人类基因组广泛关联研究。还进行了初步实验，将核苷酸代谢基因与血细胞中的端粒长度联系起来。在我们的实验室进行的实验表明，核苷酸的遗传和小分子扰动新陈代谢可以快速而有力地改变人类细胞的端粒长度，包括诱导多能干细胞然而，这两种机制都存在基础知识空白。这种效应的背后，以及操纵核苷酸代谢是否可以改变端粒的维持造血系统，这可能具有治疗作用，在这里，我们的目标是揭示核苷酸如何发挥作用。新陈代谢扰动会改变人类细胞的端粒长度，包括人类的体外和体内模型这项研究包括两个目的：（1）如何改变核苷酸代谢基因。影响端粒维持，以及（2）小分子操纵核苷酸代谢如何改变端粒稳态，在人类细胞中，包括初级造血干细胞和祖细胞。获得奖项后，PI 设计了一项研究策略和培训计划，将为他提供：（1）基础知识代谢组学、生物信息学和端粒生物学方面的专业知识，(2) 由导师和专家组成的专家组合作者不仅要提升研究专业知识，还要提升整个职业生涯的学术技能，包括资助和科学交流，以及 (3) 从事以翻译为中心的血液学研究的经验为他作为医生科学家的职业目标做准备的研究该提案将在富人和富人中进行。哈佛医学院和波士顿儿童医院的合作研究环境完成。预计工作将确立核苷酸代谢作为人类端粒稳态的关键调节剂，对治疗包括骨髓在内的需求未得到满足的造血系统疾病的治疗意义衰竭和再生障碍性贫血，以及其他非造血系统退行性疾病。