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

(PQ5) Contribution of mitochondrial pathways to metabolic heterogeneity in molecular subtypes of Diffuse Large B Cell Lymphoma

(PQ5) 线粒体途径对弥漫性大 B 细胞淋巴瘤分子亚型代谢异质性的贡献

基本信息

批准号：
10471847
负责人：
Nika N Danial
金额：
$ 54.69万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471847
关键词：
Address Architecture B-Cell Antigen Receptor B-Cell Lymphomas Biochemical Biochemical Genetics Carbon Cell physiology Complement Consumption Coupled Data Development Diabetes Mellitus Dissection Energy Metabolism Equilibrium Genetic study Glycolysis Growth Heterogeneity Human In Vitro Individual Investigation Label Learning Link Lipids Lymphoma Malignant Neoplasms Mass Spectrum Analysis Metabolic Metabolic Diseases Metabolism Mitochondria Molecular Morphology Obesity Outcome Oxides Pathway interactions Pattern Process Protein Dynamics Proteins Receptor Inhibition Receptor Signaling Regulation Research Role Shapes Signal Transduction Testing Tracer Tumorigenicity base clinically relevant fatty acid oxidation genetic approach high resolution imaging in vivo inhibitor insight large cell Diffuse non-Hodgkin&apos s lymphoma metabolomics molecular subtypes network architecture novel novel therapeutics programs response small molecule support network tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY The mitochondrial network is shaped by fusion and fission dynamics that ultimately influence the mitochondrial capacity to utilize fuels. Our recent dissection of metabolic circuits in diffuse large B-cell lymphoma (DLBCL) has identified heterogeneity of mitochondrial architecture and biochemical networks in DLBCL subtypes with distinct patterns of fuel utilization. OxPhos-DLBCLs show a net increase in mitochondrial fragmentation and rely on mitochondrial fatty acid oxidation (FAO) for survival and proliferation independent of B-cell receptor (BCR) signaling. This is distinct from non-OxPhos/Warburg type DLBCLs that are BCR-dependent, rely on glycolysis and have connected mitochondrial network. Importantly, blocking fragmentation in OxPhos-DLBCLs reduces mitochondrial FA utilization capacity but does not alter consumption of other fuels. The above observations indicate a specific requirement for fragmentation in facilitating mitochondrial handling of FAs, and link mitochondrial morphologic heterogeneity to fuel choice and metabolic specialization in DLBCL subtypes. In response to RFA-CA-17-017 PQ5, the proposed studies examine the mechanisms and consequences of this link and its relevance to tumorigenesis. In Aim 1, we will define the mechanistic determinants of the net increase in mitochondrial fragmentation in OxPhos- vs BCR-DLBCLs, including changes in fusion and fission rates at the level of individual mitochondria and alterations in mitochondria-shaping proteins. We will also address the long-term consequences of altered mitochondrial fragmentation in growth and survival of DLBCL subtypes in vitro and in vivo. In Aim 2, we will learn about the consequence of mitochondrial fragmentation for fuel utilization in general and FAO in particular. A combination of carbon tracing and biochemical studies will be undertaken to determine the mechanisms underlying regulation of mitochondrial FA handling by mitochondrial fragmentation in OxPhos-DLBCLs. In Aim 3, we will determine how mitochondrial architecture and fuel metabolism are modulated by BCR-initiated signals, and probe the relevance of these mitochondrial pathways to the sensitivity of BCR-DLBCLs to clinically-relevant BCR inhibitors. Together, these studies can provide important conceptual advancement and mechanistic insights into how the mitochondrial morphologic specializations in DLBCLs are intertwined with fuel utilization to support tumor growth.

项目总结