权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of PPM1D and PPM1D mutations in hematopoiesis and response to stress

PPM1D 和 PPM1D 突变在造血和应激反应中的作用

基本信息

批准号：
10472614
负责人：
Peter Grant Miller
金额：
$ 22.33万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-02 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10472614
关键词：
Address Advisory Committees Affect Alleles Amino Acids Animals Backcrossings Binding Biochemical Biochemical Pathway Biological Biological Models Biological Process Biology Biometry Blood C-terminal Cells Chemoresistance Chemotherapy and/or radiation Clinical Collaborations Communities Complex Cytotoxic Chemotherapy DNA Damage Dana-Farber Cancer Institute Data Development Development Plans Disease Educational process of instructing Environment Exposure to Genes Genetic Screening Goals Hematologic Neoplasms Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Human Impairment Individual Inflammation Institutes International Knock-in Knock-in Mouse Knock-out Lead Light MAP Kinase Gene Malignant Neoplasms Mass Spectrum Analysis Mediating Mentorship Modeling Molecular Mus Mutate Mutation Myeloproliferative disease Neoplasms Oncologist Oncology Pathway interactions Patient Care Patients Phenotype Physicians Play Poly I-C Prevalence Protein Dephosphorylation Protein Inhibition Protein Serine/Threonine Phosphatase Protein phosphatase Proteins Proteomics Radiation Recurrence Reporter Research Research Personnel Resistance Role Scientist Stress System TP53 gene Techniques Testing Time Training Translational Research Transplantation Ubiquitin Ubiquitination Work career career development chemotherapy clinical practice cytotoxic experimental study hematopoietic stem cell self-renewal human disease insight leukemia mature animal mouse model multicatalytic endopeptidase complex mutant novel novel therapeutics protein degradation protein expression protein function response self-renewal stem cell biology stem cell self renewal therapeutic target therapy development tumorigenesis ubiquitin ligase ubiquitin-protein ligase vector

项目摘要

Project Summary PPM1D encodes for a serine/threonine phosphatase that is recurrently amplified and mutated in a wide range of cancers. We have shown that recurrent C-terminal truncations impair PPM1D degradation by the proteasome, leading to increased protein levels and activity, and are common in clonal hematopoiesis and myeloid malignancies after the receipt of chemotherapy. However, the role that PPM1D plays in hematopoiesis during steady state and under conditions of stress, and the molecular mechanism by with PPM1D is degraded via the C-terminus remains unclear. We developed two novel mouse models to study PPM1D and now propose in Aim 1 to use these models to investigate how PPM1D loss and PPM1D activation via C-terminal truncation affect normal hematopoiesis and hematopoiesis in the setting of radiation and inflammation. I have also performed a genetic screen and found that UBE3C, an E3 ubiquitin ligase, regulates the levels of PPM1D and propose in Aim 2 to determine how UBE3C degrades PPM1D via interactions with the C-terminus and to define the broader ubiquitin ligase complex regulating PPM1D ubiquitination and degradation by the proteasome. Collectively, this work will help explain the prevalence of PPM1D mutations in clonal hematopoiesis and therapy-related myeloid malignancies, define the molecular machinery that regulates PPM1D levels, and shed light on PPM1D as a potential therapeutic target. The applicant, Dr. Peter Miller, is an oncologist at the Dana-Farber Cancer Institute (DFCI). He spends 80% of his time in translational research and 20% in clinical practice caring for patients with cancer. He has outlined a five-year career development plan to meet his goal of becoming an independent investigator in translational research. Dr. Miller has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. He has established collaborations with expertise in hematopoiesis, mouse models, the ubiquitin proteasome system, mass spectrometry, and applied biostatistics to provide experimental advice and specific training in the field. Dr. Miller will conduct this research at the DFCI and leverage the exceptional research and teaching environment at the DFCI, Harvard, and the Broad Institute. The DFCI, which harbors an outstanding research community and has a long track record for successful mentorship of independent physician scientists, is an ideal environment for completion of these experiments and the realization of Dr. Miller's long-term career goal of being an independent physician-scientist.

项目总结