Understanding the Role of kB Ras Proteins in Signaling and Development

了解 kB Ras 蛋白在信号传导和发育中的作用

• 批准号: 8187554
• 负责人: Sankar Ghosh
• 金额: $ 40.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-16 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187554
• 关键词: Affect; Anchorage-Independent Growth; Animals; Apoptosis; Architecture; Arthritis; Asthma; Binding; Biological; Biological Process; Biology; Birth; Breathing; Cell physiology; Cells; Cellularity; Chronic; Collagen Arthritis; Complex; Defect; Development; Disease; Dissociation; Economic Inflation; Factor Analysis; GTPase-Activating Proteins; Gene Expression; Goals; Growth; Growth Factor; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Histopathology; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Lead; Link; Lung; Malignant Neoplasms; Mediating; Molecular; Molecular Profiling; Monomeric GTP-Binding Proteins; Mus; Names; Newborn Infant; Outcome; Pathway interactions; Phenotype; Physiological; Play; Process; Production; Protein Family; Proteins; RAS genes; Regulation; Reporting; Research Proposals; Respiratory physiology; Role; Septic Shock; Signal Transduction; Staging; Stimulus; TNF gene; Testing; base; cytokine; extracellular; in vivo; inhibitor/antagonist; insight; interest; lung development; macrophage; member; mouse model; novel; overexpression; protein B; protein complex; ral A GTP-Binding Protein; ras Proteins; research study; response; surfactant; transcription factor

DESCRIPTION (provided by applicant): The goal of this project is to understand how (B-Ras1 and (B-Ras2, members of an unusual sub-class of Ras-like proteins, are regulated, and how they in turn regulate pathways leading to NF-(B and Ral GTPases. These proteins were originally discovered through their physical interaction with the I(B( protein, and in vitro and overexpression experiments indicated that they are inhibitors of NF-(B. However the true physiological role of these proteins has remained unclear. Our preliminary results using knock-outs of both (B-ras genes shows that they act to inhibit both NF-(B and Ral GTPase pathways. Interestingly, mice lacking (B-Ras proteins also die perinatally due to defects in lung development. In this research proposal we aim to ask the following questions. In Aim 1 we will study how (B-Ras actually regulates NF-(B. While affecting the stability of I(B( is a likely mechanism, many questions about exactly how (B-Ras functions remains unanswered. Availability of cells lacking (B-Ras will allow us to explore the underlying mechanism in a systematic manner. We will also use mice lacking (B-Ras in macrophages to study mouse models of inflammation including septic shock and collagen-induced arthritis. In Aim 2 we will ask how (B-Ras regulates Ral, and determine whether activated Ral contributes to NF-(B activation. We will study the mechanism by which growth factor signaling disrupts the (B-Ras-RalGAP complex, and determine why binding to (B-Ras inhibits the activity of RalGAP. We will also test whether the activated Ral in (B-Ras deficient cells contributes to NF-(B activation. Finally in Aim 3 we will explore the lung phenotype seen in the (B-Ras-deficient animals. We will study the mechanism of dysregulated surfactant expression, in particular the role of NF-(B in the process. In summary these studies will provide significant new insight into the biology of these evolutionarily conserved, yet enigmatic, members of this Ras-like family of proteins. PUBLIC HEALTH RELEVANCE: Chronic inflammation underlies many diseases such as arthritis, asthma and cancer. The transcription factor NF-(B plays a key role in regulating inflammation and understanding the molecular mechanism that regulates NF-(B is of great interest. In this proposal we will determine how (B-ras proteins regulate the activity of NF-(B and Ral GTPases, and determine why lack of (B-Ras leads to defects in lung development.

描述（由申请人提供）：该项目的目的是了解（B-RAS1和（B-RAS2，不寻常的类似RAS蛋白的子类的成员）如何受到调节，以及它们如何调节导致NF-的途径（B和RAL GTPases）（B和RAL GTPases）（这些蛋白质的实际相互作用。 of NF-(B. However the true physiological role of these proteins has remained unclear. Our preliminary results using knock-outs of both (B-ras genes shows that they act to inhibit both NF-(B and Ral GTPase pathways. Interestingly, mice lacking (B-Ras proteins also die perinatally due to defects in lung development. In this research proposal we aim to ask the following questions. In Aim 1 we will study how （B-RAS实际上调节NF-（b。在影响I的稳定性的同时（B（可能是一种可能的机制），许多有关如何确切的问题（B-RAS函数仍未得到解答。缺乏细胞的可用性（B-RAS将使我们能够以系统的方式探索潜在的机制。 We will also use mice lacking (B-Ras in macrophages to study mouse models of inflammation including septic shock and collagen-induced arthritis. In Aim 2 we will ask how (B-Ras regulates Ral, and determine whether activated Ral contributes to NF-(B activation. We will study the mechanism by which growth factor signaling disrupts the (B-Ras-RalGAP complex, and determine why binding to (B-Ras inhibits the activity of ralgap。我们还将测试（B-RAS缺乏的细胞中的激活RAL（B激活）（b激活。最终在目标3中，我们都将在（B-RAS缺乏的动物）中看到的肺表型。我们将研究不正常的表面表达的机制，尤其是在这些研究中提供了这些研究的作用。这个类似Ras的蛋白质家族的成员神秘。 公共卫生相关性：慢性炎症是许多疾病，例如关节炎，哮喘和癌症。转录因子NF-（B在调节炎症和理解调节NF-的分子机制中起关键作用（B非常有趣。在该提案中，我们将确定如何确定（B-RAS蛋白调节NF-（B和RAL GTPases）的活性（B和RAL GTPase的活性），并确定缺乏（B-RAS导致Lung Developments in Lung Developments Fealects defects。