Functional Anatomy of Mammalian Phosphatidylinositol Transfer Proteins

哺乳动物磷脂酰肌醇转移蛋白的功能解剖学

基本信息

批准号：
9262952
负责人：
Vytas A Bankaitis
金额：
$ 42.17万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-05 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262952
关键词：
Acute Address Alleles Anatomy Anderson syndrome Animal Model Binding Biochemical Biological Biological Assay Biological Process Biology Birth Cell Death Cell membrane Cell model Cell physiology Cells Chemicals Collection Communities Computer Simulation Data Defect Development Diagnosis Disease Disease model Diversity Library Down-Regulation Embryonic Development Endothelial Cells Enzymes Epidermal Growth Factor Receptor Eukaryota Evaluation Failure Family Fatty Liver Fluorescence Fluorescence Resonance Energy Transfer Growth Factor Human Hypoglycemia Image In Vitro Individual Inositol Phosphates Investigation Knockout Mice Knowledge Laboratories Lead Lipids Lipodystrophy Malignant Neoplasms Mammalian Cell Mammals Mammary Neoplasms Mechanics Membrane Metabolic Metabolism Modeling Mus Neonatal Nerve Degeneration Nervous System Trauma Neuraxis Neurodegenerative Disorders Neurologic Deficit Operative Surgical Procedures Outcome PDGF receptor tyrosine kinase Peripheral Nervous System Pharmacologic Substance Pharmacology Phenotype Phosphatidylinositol Transfer Protein Phosphatidylinositols Phospholipase C Phospholipid Transfer Proteins Phospholipids Phosphotransferases Physiological Platelet-Derived Growth Factor Receptor Play Process Production Protein Conformation Protein Isoforms Protein Tyrosine Kinase Proteins Reaction Reagent Receptor Protein-Tyrosine Kinases Receptor Signaling Recruitment Activity Regulation Research Resistance Retinal Degeneration Role Second Messenger Systems Series Signal Pathway Signal Transduction Signal Transduction Pathway Solvents Specificity Sum Surface Systems Analysis Testing Translating Tumor Angiogenesis Work Yeasts Zebrafish base biophysical techniques cancer therapy cell growth design experimental study fascinate fly human disease inhibitor/antagonist innovation inorganic phosphate loss of function member morphogens nervous system disorder novel novel strategies phosphatidylcholine transfer protein premature protein function public health relevance quantitative imaging receptor response screening single molecule small molecule inhibitor tool tumor

项目摘要

DESCRIPTION (provided by applicant): The objective of this research is to undertake a detailed analysis of an under-investigated class of proteins: the mammalian phosphatidylinositol/phosphatidylcholine transfer proteins (PITPs). The functions and mechanisms of mammalian PITP function remains to be elucidated. The research plan is designed to identify mechanisms of function of specific mammalian PITP isoforms - the Class 1 PITPs. This proposal is founded on our creation and characterization of a PITP knockout mouse and an allelic series of mice with graded defects in function of this protein. The pitp0/0 mouse and its derivatives are attractive disease models in that these are born alive, but manifest powerful phenotypes after birth. These phenotypes permit collection of defined cell-based reagents for analysis. Using these unique animal and cellular models as primary analytical subjects, we will undertake three lines of investigation. First, we will use sophisticaed biochemical and biophysical approaches to decipher how Class 1 PITPs function at the level of single molecules. Second, we will use sophisticated and quantitative imaging and analytical assays to determine how Class 1 PITPs functionally engages signaling receptor tyrosine kinases such as epidermal growth factor receptor and platelet-derived growth factor receptor. The appropriate activity of these receptors is required for proper cell growth control and morphogen responses. Derangements lead to cancer and neurological deficits. Third, we will exploit a powerful screening platform we assembled for the purpose of identifying and validating small molecule inhibitors with high specificity for Class 1 PITPs. Such reagents would be of value as tool compounds for surgical manipulation of phosphoinositide signaling in cells, and hold the potential of identifying lead compounds for new pharmaceuticals directed at treatment of cancer or neurological deficits. PITPs play central roles in regulating signal transduction pathways that interface with diverse cellular processes. Yet, the underlying mechanisms are not understood because these have not been investigated. The Bankaitis laboratory is uniquely poised to address questions of mechanism of Class 1 PITP function as it has developed unique experimental systems for analysis.

描述（由适用提供）：这项研究的目的是对不足的蛋白质类别进行详细分析：哺乳动物磷脂酰肌醇/磷脂酰胆碱转移蛋白（PITPS）。哺乳动物PITP功能的功能和机制尚待阐明。该研究计划旨在确定特定哺乳动物PITP同工型的功能机理 - 1类PITP。该建议建立在我们的创建和表征pitp敲除小鼠和该蛋白质功能分级缺陷的小鼠小鼠的表征上。 pitp0/0 小鼠及其衍生物是有吸引力的疾病模型，因为它们是生命的，但出生后表现出强大的表型。这些表型允许收集定义的基于细胞的试剂进行分析。我们将使用这些独特的动物和细胞模型作为主要的分析主题，我们将进行三条投资。首先，我们将使用复杂的生化和生物物理方法来解密1类PITP在单分子水平上的作用。其次，我们将使用复杂的定量成像和分析测定来确定1类PITP如何在功能上与信号受体酪氨酸激酶（如表皮生长因子受体和血小板衍生的生长因子受体受体）相关。这些受体的适当活性是正确的细胞生长控制和形态学反应所必需的。危险导致癌症和神经系统缺陷。第三，我们将利用一个强大的筛选平台，以识别和验证对1类PITP的高特异性的小分子抑制剂的目的。这种试剂将作为对细胞中磷酸肌醇信号的手术操纵的工具化合物的价值，并具有鉴定针对治疗癌症或神经学缺陷的新药物的铅化合物的潜力。 PITP在控制与大型细胞过程接口的信号转导途径中起着核心作用。然而，由于尚未研究这些机制，因此尚不清楚基本机制。 Bankaitis实验室被中毒，可以解决1类PITP功能机理问题，因为它已经开发了独特的实验系统进行分析。