ABERRANT JAK-STAT SIGNALING DUE TO LNK MUTATIONS IN MYELOPROLIFERATIVE NEOPLASMS

骨髓增生性肿瘤中 LNK 突变导致 JAK-STAT 信号异常

基本信息

批准号：
9088503
负责人：
Stephen Tracy Oh
金额：
$ 15.5万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088503
关键词：
Acute leukemia Adaptor Signaling Protein Address Advisory Committees Affect Alleles Back Basic Science Binding Biological Assay Blast Phase Bone Marrow Cells CD34 gene Cancer Biology Cell Line Cell Lineage Cell membrane Cells Clinical Co-Immunoprecipitations Colony-forming units Confocal Microscopy Core Facility Cytokine Activation Development Disease Doctor of Philosophy Dominant-Negative Mutation Environment Erythrocytoses Exhibits Exons Family Feedback Flow Cytometry Frequencies Genetic Goals Growth Hematologic Neoplasms Hematology Hematopoiesis Hematopoietic stem cells Hemorrhagic Thrombocythemia Heterozygote Investigation JAK2 gene Laboratories Lead Leukocytosis Link MPL gene Mentors Morbidity - disease rate Mus Mutation Myelogenous Myeloproliferative disease Normalcy PH Domain Pathogenesis Pathway interactions Patients Phenotype Physicians Play Polycythemia Vera Primary Myelofibrosis Principal Investigator Proline Property Proteins Regulation Regulatory Element Research Research Personnel Resources Role Sampling Scientist Signal Transduction Somatic Mutation Splenomegaly Structure Terminator Codon Thrombopoietin Training Training Programs Transplantation Tyrosine Universities Variant Washington Work career cellular transduction cohort collaborative environment cytokine effective therapy feeding follow-up in vivo insight member mouse model mutant novel platelet protein P47 post-doctoral training progenitor programs retroviral transduction src Homology Region 2 Domain

项目摘要

DESCRIPTION (provided by applicant): This proposal outlines a 5-year training program for the successful transition of the investigator to an independent physician-scientist. The principal investigator completed Ph.D. and postdoctoral training in cancer biology and signal transduction, as well as structured clinical training in hematology, and plans to pursue an academic career investigating the pathogenesis of hematologic malignancies. The training plan proposed here will expand upon his clinical and scientific background and provide him access to a supportive environment that will prepare him for a career as an independent investigator. The research program described here focuses on the functional characterization of LNK mutations in myeloproliferative neoplasms (MPNs). The applicant will be mentored by Dr. Dan Link, a recognized leader in the investigation of normal and leukemic hematopoiesis. An advisory committee consisting of basic science and clinical/translational experts in hematology will provide additional scientific and career advice. Dysregulated JAK-STAT signaling is a hallmark of MPNs. Recent work has led to the identification of novel mutations in LNK, a negative regulator of JAK-STAT signaling, in MPNs. Therefore, the aims of this proposal are to determine the mechanisms by with LNK mutations modulate JAK-STAT signaling, and to characterize the ability of LNK mutations to contribute to MPN pathogenesis. To accomplish these goals, the investigator will evaluate JAK-STAT signaling in cell lines, murine bone marrow cells, and primary cells from MPN patients bearing LNK mutations. In addition, murine models will be developed, in order to determine how LNK mutations contribute to the development of myeloproliferatve disease in vivo. These studies will provide new mechanistic insights in the pathogenesis of MPNs, and potentially lead to the development of more effective treatment options for patients with MPNs. The applicant's laboratory is well equipped for these studies, and Washington University provides a rich environment for the training and development of the investigator. Access to core facilities and other scientific resources, as well as availability of clinical samples, is exceptional. Thus, the proposed studies and training environment will facilitate the candidate's long-term goal to become a successful independent investigator.

描述（由申请人提供）：该提案概述了一个为期 5 年的培训计划，旨在使研究者成功过渡为独立的医师科学家。主要研究者完成了博士学位。癌症生物学和信号转导方面的博士后培训，以及血液学方面的结构化临床培训，并计划从事研究血液恶性肿瘤发病机制的学术生涯。这里提出的培训计划将扩展他的临床和科学背景，并为他提供支持性环境，为他作为独立研究者的职业生涯做好准备。这里描述的研究项目重点关注骨髓增生性肿瘤 (MPN) 中 LNK 突变的功能特征。申请人将得到 Dan Link 博士的指导，他是正常和白血病造血研究领域公认的领导者。由血液学基础科学和临床/转化专家组成的咨询委员会将提供额外的科学和职业建议。 JAK-STAT 信号传导失调是 MPN 的一个标志。最近的工作发现了 MPN 中 LNK 的新突变，LNK 是 JAK-STAT 信号传导的负调节因子。因此，本提案的目的是确定 LNK 突变调节 JAK-STAT 信号传导的机制，并表征 LNK 突变促进 MPN 发病机制的能力。为了实现这些目标，研究人员将评估携带 LNK 突变的 MPN 患者的细胞系、小鼠骨髓细胞和原代细胞中的 JAK-STAT 信号传导。此外，还将开发小鼠模型，以确定 LNK 突变如何促进体内骨髓增生性疾病的发展。这些研究将为 MPN 的发病机制提供新的机制见解，并有可能为 MPN 患者开发更有效的治疗方案。申请人的实验室为这些研究配备了良好的设备，华盛顿大学为研究者的培训和发展提供了丰富的环境。使用核心设施和其他科学资源以及临床样本的可用性非常出色。因此，拟议的学习和培训环境将促进候选人成为一名成功的独立研究者的长期目标。