Regulation and manipulation of the telomerase RNA component in hematopoiesis

造血过程中端粒酶 RNA 成分的调控和操作

• 批准号: 10626891
• 负责人: SUNEET AGARWAL
• 金额: $ 47.57万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626891
• 关键词: Aging; Aplastic Anemia; Biochemical; Biogenesis; Biology; Bone marrow failure; Cardiovascular Diseases; Cells; Cirrhosis; Complex; DNA Sequence Alteration; Defect; Degenerative Disorder; Development; Disease; Dyskeratosis Congenita; Exonuclease; Failure; Functional disorder; Genetic Diseases; Genetic study; Goals; Hand; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Impairment; Knowledge; Length; Liver Fibrosis; Liver diseases; Logic; Longevity; Lung diseases; Medical; Moon; Mus; Mutation; Outcome; Pathway interactions; Patients; Play; Polymerase; Pulmonary Fibrosis; RNA; Regulation; Research; Ribonucleoproteins; Role; Specificity; Structure; Systemic Therapy; Techniques; Telomerase; Telomerase RNA Component; Telomere Maintenance; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Untranslated RNA; Work; Xenograft Model; curative treatments; efficacy evaluation; exhaustion; genetic approach; human disease; human model; human stem cells; humanized mouse; in vivo; induced pluripotent stem cell; inhibitor; inhibitor therapy; innovation; leukemia; novel; novel strategies; novel therapeutics; self-renewal; small molecule; small molecule inhibitor; stem cell function; stem cells; telomere; therapeutic development; therapeutically effective; therapy development; tool; transcriptome

PROJECT SUMMARY/ABSTRACT Telomerase is critical for health and longevity, but there is a fundamental lack of understanding of how it is regulated in human cells. This knowledge gap impedes the ability to develop therapies for a growing spectrum of disorders in which telomerase dysfunction is implicated. The long-term goal of this project is to be able to manipulate telomerase in human cells for therapeutic benefit, with a key target being the hematopoietic system. The level of the noncoding telomerase RNA component TERC is a critical determinant of telomerase function in cells. Low TERC levels resulting from genetic mutations cause a wide spectrum of degenerative disorders, including dyskeratosis congenita (DC), aplastic anemia, MDS/leukemia, cardiovascular disease, pulmonary fibrosis, and cirrhosis. Recent work identifies the non-canonical polymerase PAPD5 as a key negative regulator of TERC. PAPD5 is thus a novel target for small molecule inhibitors to restore TERC and telomeres in human diseases. What is not known is the basis of selective regulation of non-coding RNAs (ncRNAs) by PAPD5, nor whether inhibiting PAPD5 will be therapeutically effective. The overall objectives of this proposal are (1) to understand how PAPD5 selectively regulates ncRNAs, and (2) to determine the in vivo efficacy of PAPD5 inhibitors in restoring hematopoietic stem cell (HSC) function. The central hypothesis is that PAPD5 selectively regulates TERC and a small number of ncRNAs, providing a therapeutic window for systemic PAPD5 inhibition to restore telomeres and self-renewal capacity in stem cells. The rationale for our work is that understanding mechanisms of selectivity and demonstrating therapeutic efficacy of small molecule PAPD5 inhibitors will provide a strong scientific framework for their development as treatments for bone marrow failure and a range of diseases. The central hypothesis will be tested by pursuing two Specific Aims: (1) Identify the mechanisms of selective regulation of ncRNAs by PAPD5, and (2) Determine the therapeutic efficacy of PAPD5 inhibitors in vivo. Under the first aim, biochemical and genetic approaches will be used to rigorously identify bona fide PAPD5 targets, and to decipher the regulatory logic of the PAPD5-dependent transcriptome in human cells, emphasizing HSCs. Tools and techniques that have been developed and demonstrated to be feasible in the applicants’ hands will be used. Under the second aim, the therapeutic efficacy of small molecule PAPD5 inhibitors to restore telomere maintenance and HSC function in vivo will be determined. New approaches to overcome interspecies differences in telomere biology and model human HSC failure will be applied. The approach is innovative because PAPD5 is a long-sought, novel and tractable target regulating TERC, the inhibition of which may enable a systemic telomerase-modulating therapy that selectively impacts stem cells. The proposed research is significant, because it is expected to yield new strategies to manipulate telomerase in a growing number of hematopoietic and degenerative disorders including aplastic anemia, MDS/leukemia, pulmonary and cardiovascular disease, in which telomerase dysfunction is implicated but for which there are few if any curative therapies.

项目总结/摘要 端粒酶对健康和长寿至关重要，但对它的作用机制缺乏基本的了解。 在人体细胞中调节。这种知识差距阻碍了为越来越多的疾病谱开发治疗方法的能力 与端粒酶功能障碍有关的疾病。该项目的长期目标是能够 操纵人类细胞中的端粒酶以获得治疗益处，关键目标是造血系统。 非编码端粒酶RNA组分TERC的水平是端粒酶功能的关键决定因素， 细胞由基因突变引起的低TERC水平导致广泛的退行性疾病， 包括先天性角化不良（DC）、再生障碍性贫血、MDS/白血病、心血管疾病、肺 纤维化和肝硬化。最近的工作确定了非典型聚合酶PAPD 5作为一个关键的负调节因子 关于TERC因此，PAPD 5是小分子抑制剂恢复人类TERC和端粒的新靶点 疾病目前尚不清楚的是PAPD 5选择性调节非编码RNA（ncRNA）的基础，也不清楚PAPD 5是否能调节非编码RNA（ncRNA）。 抑制PAPD 5是否在治疗上有效。本建议的总体目标是：（1） 了解PAPD 5如何选择性地调节ncRNA，以及（2）确定PAPD 5的体内功效 造血干细胞（HSC）功能的抑制剂。核心假设是PAPD 5 选择性地调节TERC和少量ncRNA，为全身性肿瘤提供治疗窗口。 PAPD 5抑制恢复干细胞中的端粒和自我更新能力我们工作的基本原理 是理解选择性的机制和证明小分子PAPD 5的治疗效果 抑制剂将为它们作为骨髓衰竭治疗方法的发展提供强有力的科学框架 和一系列疾病。中心假设将通过追求两个具体目标来检验：（1）确定 通过PAPD 5选择性调节ncRNA的机制，以及（2）确定 体内PAPD 5抑制剂。在第一个目标下，生物化学和遗传学方法将被用来严格地 识别真正的PAPD 5靶点，并破译PAPD 5依赖性转录组的调控逻辑， 人类细胞，强调HSC。已开发并证明有效的工具和技术 在申请人手中可行的将被使用。在第二个目标下，小分子药物的治疗效果 将确定PAPD 5抑制剂在体内恢复端粒维持和HSC功能。新方法 以克服端粒生物学中的种间差异并建立人HSC衰竭模型。的 这种方法是创新的，因为PAPD 5是一种长期寻找的，新颖的和易处理的调节TERC的靶点， 其抑制可实现选择性影响干细胞的全身性端粒酶调节疗法。 这项研究具有重要意义，因为它有望产生新的策略来操纵端粒酶， 越来越多的造血和变性疾病包括再生障碍性贫血，MDS/白血病， 肺和心血管疾病，其中涉及端粒酶功能障碍，但很少有 如果有治愈性疗法的话

项目成果

Telomerase RNA processing: Implications for human health and disease.

• DOI: 10.1002/stem.3270
• 发表时间: 2020-09-01
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Nagpal N;Agarwal S
• 通讯作者: Agarwal S

Poly(A)-specific ribonuclease (PARN) mediates 3'-end maturation of the telomerase RNA component.

• DOI: 10.1038/ng.3423
• 发表时间: 2015-12
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Moon DH;Segal M;Boyraz B;Guinan E;Hofmann I;Cahan P;Tai AK;Agarwal S
• 通讯作者: Agarwal S

Domain specific mutations in dyskerin disrupt 3' end processing of scaRNA13.

• DOI: 10.1093/nar/gkac706
• 发表时间: 2022-09-09
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Nagpal, Neha;Tai, Albert K.;Nandakumar, Jayakrishnan;Agarwal, Suneet
• 通讯作者: Agarwal, Suneet

Spectrum of Liver Pathology in Dyskeratosis Congenita.

先天性角化不良的肝脏病理学谱。

• DOI: 10.1097/pas.0000000000002060
• 发表时间: 2023
• 期刊: The American journal of surgical pathology
• 作者: Putra,Juan;Agarwal,Suneet;Al-Ibraheemi,Alyaa;Alomari,AhmadI;Perez-Atayde,AntonioR
• 通讯作者: Perez-Atayde,AntonioR

Successful cord blood transplantation for del7q myelodysplastic syndrome in Pearson marrow pancreas syndrome.

成功进行脐带血移植治疗皮尔逊骨髓胰腺综合征中的 del7q 骨髓增生异常综合征。

• DOI: 10.1002/ajh.27107
• 发表时间: 2023
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Belgacem,ZachariaH;Dubois,SoniaM;Jacoby,Elad;Martin,PaulL;Parikh,SumitB;Fleming,MarkD;Agarwal,Suneet
• 通讯作者: Agarwal,Suneet