Targeting Fnip1 to disrupt B cell development, metabolism, and transformation

靶向 Fnip1 破坏 B 细胞发育、代谢和转化

基本信息

批准号：
8966007
负责人：
BRIAN M IRITANI
金额：
$ 39.54万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8966007
关键词：
Activated Lymphocyte Address Amino Acids Antibodies Antigen Receptors Apoptosis Autoantibodies Autoimmune Diseases Autophagocytosis B cell differentiation B-Cell Development B-Cell Lymphomas B-Lymphocytes Binding Biochemical Genetics Biogenesis Biological Process Cancer Cell Growth Cell Death Cell Survival Cell division Cell physiology Cells Cellular Metabolic Process Chemicals Citric Acid Cycle Clinical Co-Immunoprecipitations Consumption Cre-LoxP Development Diabetes Mellitus Digestion Ensure Equilibrium Ethylnitrosourea Exhibits Exposure to FRAP1 gene Family Fatty Acids Folliculin Glucose Glutamine Glycolysis Goals Health Homeostasis Human Immune Immunoglobulin M Knockout Mice Label Lead Ligation Link Lipids Lymphocyte Lymphocyte Activation Lymphoid Tissue Lymphoma Lymphomagenesis Lysosomes MYC gene Malignant Neoplasms Mature B-Lymphocyte Measures Mediating Metabolic Metabolic Control Metabolic Diseases Metabolic stress Metabolism Microscopy Mission Mitochondria Molecular Mouse Strains Mus Muscular Dystrophies Mutagenesis Nucleotides Nutrient Obesity Oncogene Activation Organelles Oxidative Phosphorylation Patients Peripheral Process Production Proteins Public Health Research Resolution Rest Role Scaffolding Protein Signal Pathway Signal Transduction Staging Stress Surface T-Cell Development Technology Testing Transgenic Mice Transgenic Organisms United States National Institutes of Health Warburg Effect adenylate kinase aerobic glycolysis base c-myc Genes cancer cell cell growth cell motility cell transformation chemotherapeutic agent chemotherapy crosslink efficacy testing energy balance exhaustion genetic approach inhibitor/antagonist innovation killer T cell killings leukemia/lymphoma metabolic profile metabolomics mouse model neoplastic cell novel novel strategies nutrient deprivation peripheral blood response sensor transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Relative to resting lymphocytes, both activated lymphocytes and cancer cells exhibit a unique shift in cell metabolism from oxidative phosphorylation, which efficiently produces energy, to aerobic glycolysis, which generates bio-precursors (such as lipids, amino acids, and nucleotides) required to fuel cell division. An understanding of the factors that control this metabolic switch (termed "Warburg effect") is highly significant because it could lead to novel strategies to selectively block lymphocyte activation in autoimmune disease, and/or inhibit cancer cell survival. In this application, we propose to investigate a novel protein called Folliculin Interacting protein-1 (Fnip1) which our studies suggest is essential for maintaining "metabolic balance" during energy and nutrient stress such as during lymphocyte activation, nutrient restriction, and oncogene activation. We identified an innovative new strain of mice lacking Fnip1 in a chemical mutagenesis screen, based on the complete absence of B lymphocytes in peripheral blood. Fnip1 null mice have blocks in pre-B cell and invariant natural killer T (iNKT) cell development at stages where the cells normally undergo massive division dependent on c-Myc, an oncogene deregulated in many cancers in humans. Remarkably, loss of Fnip1 also protects against pre-B cell lymphoma induced by c-Myc in a mouse model of Burkitt's B cell lymphoma. Although the functions of Fnip1 are unknown, it interacts with Folliculin (a protein of unknown function) and the master metabolic regulator AMP kinase, an energy sensing molecule that stimulates energy production in response to energy stress and inhibits energy-consuming anabolic processes regulated by mammalian target of rapamycin (mTOR). Our long-term goals are to determine how Fnip1 functions to control the development, activation, metabolism, and transformation of lymphocytes. Our Specific Aims are: (1) To define the roles of Fnip1 in pre-B cell development and metabolism. We will utilize metabolomic, metabolic flux analysis, and transcriptomic approaches to determine whether loss of Fnip1 inhibits the "Warburg effect"; (2) To determine the importance of Fnip1 in B cell lymphoma survival and sensitivity to metabolic stress and chemotherapeutic agents. We will conditionally delete Fnip1 in primary murine B cell lymphomas and will determine consequences on tumor cell survival and signaling in response to nutrient deprivation and chemotherapy; and (3) To delineate the molecular functions of Fnip1 in autophagy and mTOR signaling pathways. We will use biochemical and genetic approaches to determine whether Fnip1 is essential to "turn off" mTOR mediated nutrient consumption, and "turn on" autophagy (self-digestion of organelles to generate nutrients) in response to nutrient deficit. These studies will address our overall innovative hypothesis that inhibition of Fnip1 "disconnects" the essential link between anabolic cell growth and aerobic glycolysis, by permitting activated lymphocytes and/or tumor cells to grow in the absence of sufficient energy and bio- substrates, resulting in "nutrient exhaustion" and cell death.

描述（由申请人提供）：相对于静息淋巴细胞，活化的淋巴细胞和癌细胞均显示出细胞代谢从氧化磷酸化的独特转变，从氧化磷酸化中，可以有效地产生能量，有效的糖酵解，从而产生了生物前体（例如脂肪，例如脂肪，氨基酸和氨基酸细胞和核细胞）。了解控制这种代谢转换（称为“ Warburg效应”）的因素非常重要，因为它可能导致新的策略有选择性地阻断自身免疫性疾病中的淋巴细胞激活，并且/或抑制癌细胞的存活。在此应用中，我们建议研究一种称为卵泡蛋白相互作用蛋白-1（FNIP1）的新型蛋白质，我们的研究认为这对于在能量和营养应激期间保持“代谢平衡”至关重要，例如淋巴细胞激活，营养限制和癌基因激活。我们根据外周血中的B淋巴细胞完全没有淋巴细胞，确定了在化学诱变筛查中缺少FNIP1的小鼠的创新新菌株。 FNIP1 NULL小鼠在前B细胞中具有块和不变的天然杀伤剂（Inkt）细胞在各个阶段发育，在这些阶段中，细胞通常会经历大规模分裂，这是c-myc的大规模分裂，这是一种在人类中许多癌症中受过的致癌基因。值得注意的是，FNIP1的丧失还可以预防伯基特B细胞淋巴瘤小鼠模型中C-MYC诱导的前B细胞淋巴瘤。尽管FNIP1的功能尚不清楚，但它与卵泡蛋白（一种功能未知的蛋白质）和主代谢调节剂AMP激酶相互作用，这是一种能量感应分子，可刺激能量应对能量应激的能量产生，并抑制能量消耗的乘型乳脂蛋白（MTOR）哺乳动物靶标（MTOR）。我们的长期目标是确定FNIP1如何控制淋巴细胞的发育，激活，代谢和转化。我们的具体目的是：（1）定义FNIP1在BER-B细胞发育和代谢中的作用。我们将利用代谢组，代谢通量分析和转录组方法来确定FNIP1的损失是否抑制了“ Warburg效应”。（2）确定FNIP1在B细胞淋巴瘤存活中的重要性以及对代谢应激和化学治疗剂的敏感性。我们将有条件地删除原发性鼠B细胞淋巴瘤中的FNIP1，并确定对肿瘤细胞存活和信号的影响，以响应营养剥夺和化学疗法；（3）描绘自噬和MTOR信号通路中FNIP1的分子函数。我们将使用生化和遗传方法来确定FNIP1是否对于“关闭” MTOR介导的营养消耗至关重要，并且“打开”自噬（对细胞器的自消化以产生营养）以响应营养不足。这些研究将解决我们整体创新的假设，即通过允许活化的淋巴细胞和/或肿瘤细胞在没有足够的能量和生物基质的情况下，抑制FNIP1“断开”将合成代谢细胞生长与有氧糖酵解之间的基本联系生长，从而导致“营养充足”和“营养耗尽”。