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

• 批准号: 10529454
• 负责人: Peter Grant Miller
• 金额: $ 17.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10529454
• 关键词: Role; PPM1D; mutations; hematopoiesis; response

Project Summary/Abstract 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.

项目概要/摘要 PPM1D 编码丝氨酸/苏氨酸磷酸酶，该酶在多种情况下反复扩增和突变 癌症。我们已经证明，反复出现的 C 末端截断会损害蛋白酶体对 PPM1D 的降解， 导致蛋白质水平和活性增加，在克隆造血和骨髓细胞中很常见 接受化疗后的恶性肿瘤。然而，PPM1D 在造血过程中发挥的作用 稳态和应激条件下，PPM1D 的分子机制通过 C 末端仍不清楚。我们开发了两种新型小鼠模型来研究 PPM1D，现在在 Aim 中提出 1 使用这些模型来研究 PPM1D 丢失和通过 C 端截断的 PPM1D 激活如何影响 正常造血和辐射和炎症环境下的造血。我还表演过一次 基因筛选发现UBE3C（一种E3泛素连接酶）调节PPM1D的水平并在Aim中提出 2 确定 UBE3C 如何通过与 C 末端的相互作用降解 PPM1D，并定义更广泛的范围 泛素连接酶复合物调节 PPM1D 泛素化和蛋白酶体降解。总的来说，这 这项工作将有助于解释克隆造血和治疗相关骨髓细胞中 PPM1D 突变的普遍性 恶性肿瘤，定义调节 PPM1D 水平的分子机制，并阐明 PPM1D 作为一种 潜在的治疗靶点。申请人Peter Miller博士是丹娜—法伯癌症研究所的肿瘤学家 （DFCI）。他将 80% 的时间花在转化研究上，20% 的时间花在照顾患有以下疾病的患者的临床实践上： 癌症。他制定了一个五年职业发展计划，以实现成为独立人士的目标 转化研究研究员。米勒博士组建了一个国际咨询委员会 公认的专家提供科学和职业指导。他与专业人士建立了合作 在造血、小鼠模型、泛素蛋白酶体系统、质谱和应用生物统计学中 提供该领域的实验建议和具体培训。米勒博士将在 DFCI 进行这项研究 并利用 DFCI、哈佛大学和布罗德研究所卓越的研究和教学环境。 DFCI 拥有杰出的研究团体，并拥有长期的成功记录 独立医师科学家的指导是完成这些实验的理想环境 实现米勒博士成为一名独立医师科学家的长期职业目标。