The Role of PPM1D in Myeloproliferative Neoplasms

PPM1D 在骨髓增生性肿瘤中的作用

基本信息

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
项目类别：
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

项目摘要

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) 是一种慢性血液系统疾病，与严重的骨髓增生性疾病相关发病率和死亡率，并有可能进展为骨髓纤维化和急变期。这些疾病其特征是一系列源自造血干细胞（HSC）水平的驱动突变，然而，目前尚不清楚驱动疾病进展的机制。目前 MPN 的治疗方法很大程度上不会改变疾病进程，因此有必要破译其潜在机制以便发现新的、更有效的治疗药物。该提案的重点是阐明磷酸酶 Mg2+/Mn2+ 依赖性 1D (PPM1D) 在 MPN 中的作用，并将其作为潜在目标进行评估预防 MPN 疾病进展。 PPM1D 参与 HSC 的维持和分化，并具有最近发现在部分 MPN 患者中发生突变和/或过度表达。初步数据显示 PPM1D 突变/过度表达导致 JAK2 突变 MPN 克隆的适应性增加，并且 PPM1D 抑制会消耗 MPN HSC。进一步了解 MPN 中 PPM1D 失调的后果我们将利用多管齐下的方法来完成以下目标，涉及主要 MPN 样本、人类诱导多能干细胞 (iPSC) 系和小鼠模型：(1) 描述 PPM1D 的影响 JAK2V617F+ 人造血细胞分子信号传导失调，(2) 评估体内 PPM1D 过度表达对 MPN 疾病表型的影响，(3) 确定以下疾病的治疗脆弱性 PPM1D 功能失调的 MPN 细胞。实验将采用多种技术，包括生化测定、小鼠移植模型、原代造血细胞集落测定、RNA 测序和转录组的基因分型。该提案还将评估一种针对 MPN 中的 PPM1D 的新策略。西奈山伊坎医学院助理教授 Bridget Marcellino 博士将在 MPN 领域的科学领袖 Ronald Hoffman 博士的指导下完成这些研究。她将拥有 75% 的受保护研究时间，并将获得必要的资源来完成这些研究研究。作为一个机构，西奈山是促进医师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。布里奇特还将设立一个咨询委员会由西奈山的 Eirini Papapetrou 博士和纪念斯隆·凯特琳癌症中心的 Ross Levine 博士组成威尔康奈尔医学院的 Dan Avi Landau 博士和生物统计学家 Amylou Dueck 博士和 Heidi 梅奥诊所的科西奥雷克。这里概述的职业发展计划将使 Marcellino 博士获得科学知识专业知识并提高她在手稿和资助准备方面的技能。该提案将有利于博士。马切利诺将实现她发表研究成果的短期目标和发展的长期目标作为一名医师科学家，建立一个独立的研究计划，重点是识别新颖的 MPN 中的治疗靶点。