The Role of PPM1D in Myeloproliferative Neoplasms

PPM1D 在骨髓增生性肿瘤中的作用

• 批准号: 10591741
• 负责人: Bridget Kelly Marcellino
• 金额: $ 16.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-20 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591741
• 关键词: Advisory Committees; Apoptosis; Automobile Driving; Biochemical; Biological Assay; Blast Phase; Blood Cell Count; C-terminal; Cell Line; Cell Proliferation; Cells; Chronic; Clinic; Collaborations; DNA Damage; Data; Dependence; Development; Development Plans; Disease; Disease Progression; Drug Targeting; Fostering; Functional disorder; Genes; Genetic Transcription; Genotype; Goals; Grant; Hematological Disease; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; Histopathology; Human; Institution; JAK2 gene; Lead; MAP Kinase Gene; Maintenance; Malignant - descriptor; Manuscripts; Memorial Sloan-Kettering Cancer Center; Mentorship; Molecular; Morbidity - disease rate; Mus; Mutate; Mutation; Myelofibrosis; Myeloproliferative disease; Natural History; PI3K/AKT; PTPN6 gene; Pathologic; Pathway interactions; Patients; Pharmaceutical Chemistry; Phase; Phosphoric Monoester Hydrolases; Physicians; Polycythemia Vera; Population; Preparation; Prognosis; Protein Serine/Threonine Phosphatase; Protein phosphatase; Publishing; Research; Resources; Role; Sampling; Scientist; Series; Signal Pathway; Signal Transduction; Specimen; TP53 gene; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Transplantation; Up-Regulation; Western Blotting; Work; burden of illness; career development; clinical phenotype; cytokine; disease phenotype; driver mutation; drug development; experimental study; fitness; hematopoietic differentiation; in vivo; induced pluripotent stem cell; inhibitor; insight; knock-down; medical schools; mortality; mouse model; mutant; neoplasm therapy; new therapeutic target; novel; novel strategies; overexpression; prevent; professor; programs; response; retroviral transduction; single-cell RNA sequencing; skills; stem cells; targeted treatment; therapeutic target; therapeutically effective; transcriptome; transcriptome sequencing; transplant model; tumor progression; tumorigenesis

Myeloproliferative Neoplasms (MPNs) are chronic hematologic disorders that are associated with significant morbidity and mortality and have the potential to progress to myelofibrosis and a blast phase. These diseases are characterized by a series of driver mutations that originate at the hematopoietic stem cell (HSC) level, however, the mechanisms driving disease progression are currently unclear. Current therapeutics for MPNs largely do not alter the disease course and it is therefore imperative to decipher the mechanisms underlying progression in order to identify new, more effective therapeutic agents. This proposal focuses on elucidating the role of Phosphatase Mg2+/Mn2+ Dependent 1D (PPM1D) in MPNs and evaluating it as a potential target to prevent MPN disease progression. PPM1D is involved in the maintenance and differentiation of HSCs and has recently been found to be mutated and/or overexpressed in a subset of MPN patients. Preliminary data shows that PPM1D mutation/overexpression leads to increased fitness of the JAK2 mutated MPN clone and that PPM1D inhibition depletes MPN HSCs. To further discern the consequences of dysregulated PPM1D in MPNs we will complete the following aims utilizing a multipronged approach involving primary MPN samples, human induced pluripotent stem cell (iPSC) lines and murine models: (1) Delineate the effects of PPM1D dysregulation on molecular signaling in JAK2V617F+ human hematopoietic cells, (2) Assess the in vivo consequences of PPM1D overexpression on MPN disease phenotype, (3) Identify therapeutic vulnerabilities of MPN cells with dysregulated PPM1D function. Experiments will employ a variety of techniques including biochemical assays, murine transplant models, primary hematopoietic cell colony assays, RNA sequencing and genotyping of transcriptomes. This proposal will also evaluate a novel strategy to target PPM1D in MPNs. Dr. Bridget Marcellino, an assistant professor at the Icahn School of Medicine at Mount Sinai, will be completing these studies under the mentorship of Dr. Ronald Hoffman, a scientific leader in the field of MPNs. She will have 75% of protected research time and will be provided the necessary resources to complete these studies. As an institution Mount Sinai is ideal for fostering the development of physician-scientists with academic seminars and state of the art facilities and resources. Bridget will also have an advisory committee consisting of Dr. Eirini Papapetrou at Mount Sinai, Dr. Ross Levine at Memorial Sloan Kettering Cancer Center, Dr. Dan Avi Landau at Weill Cornell Medical College and biostatisticians, Dr. Amylou Dueck and Heidi Kosiorek at Mayo Clinic. The career development plan outlined here will allow Dr. Marcellino to gain scientific expertise as well as increase her skills in manuscript and grant preparation. This proposal will facilitate Dr. Marcellino to achieve both her short term goal of publishing her findings and her long term goals of developing as a physician-scientist and establishing an independent research program focused on identifying novel therapeutic targets in MPNs.

骨髓增生性肿瘤（MPN）是慢性血液学疾病，其与显著的骨髓增生异常相关。 发病率和死亡率，并有可能进展到骨髓纤维化和急变期。这些疾病 特征在于起源于造血干细胞（HSC）水平的一系列驱动突变， 然而，驱动疾病进展的机制目前尚不清楚。MPN的当前治疗方法 在很大程度上不会改变疾病的进程，因此，必须破译其背后的机制， 研究进展，以确定新的，更有效的治疗药物。该提案的重点是阐明 磷酸酶Mg 2 +/Mn 2+依赖性1D（PPM 1D）在MPN中的作用，并评估其作为潜在靶点， 预防MPN疾病进展。PPM 1D参与HSC的维持和分化， 最近发现在MPN患者的亚组中突变和/或过表达。初步数据显示 PPM 1D突变/过表达导致JAK 2突变的MPN克隆的适应性增加， PPM 1D抑制耗尽MPN HSC。进一步辨别MPN中PPM 1D失调的后果 我们将利用多管齐下的方法完成以下目标，包括初级MPN样本、人类 诱导多能干细胞（iPSC）系和小鼠模型：（1）描述PPM 1D的作用 （2）评估JAK 2 V617 F+人造血细胞中分子信号传导的体内调节异常， PPM 1D过表达对MPN疾病表型的影响，（3）确定 PPM 1D功能失调的MPN细胞。实验将采用各种技术，包括 生物化学测定、鼠移植模型、原代造血细胞集落测定、RNA测序 和转录组的基因分型。该提案还将评估针对MPN中PPM 1D的新策略。 博士西奈山伊坎医学院助理教授布里奇特·马塞利诺将在 在MPN领域的科学领导者罗纳德霍夫曼博士的指导下完成这些研究。 她将有75%的受保护的研究时间，并将提供必要的资源来完成这些研究。 问题研究作为一个机构，西奈山是促进医生科学家发展的理想场所， 学术研讨会和最先进的设施和资源。布丽奇特还会有一个顾问委员会 包括西奈山的Eirini Papapetrou博士，纪念斯隆凯特琳癌症中心的Ross Levine博士 中心的Dan Avi朗道博士和生物统计学家Amylou Dueck博士和Heidi博士 我是马约诊所的科西奥雷克这里概述的职业发展计划将使Marcellino博士获得科学的 专业知识，并提高她在手稿和赠款准备的技能。这将有助于博士。 Marcellino既要实现她发表研究结果的短期目标，又要实现她发展研究的长期目标。 作为一名医生科学家，并建立了一个独立的研究计划，重点是确定新的 MPN中的治疗靶点。