ErbB Signaling in Fetal Type II Cell Growth

胎儿 II 型细胞生长中的 ErbB 信号转导

• 批准号: 7746424
• 负责人: CHRISTIANE E DAMMANN
• 金额: $ 39.64万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-10 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746424
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Birth; Blocking Antibodies; Borderline Personality Disorder; Bronchopulmonary Dysplasia; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cells; Co-Immunoprecipitations; Confocal Microscopy; Development; Developmental Cell Biology; Developmental Process; Disease; Down-Regulation; ERBB2 gene; Elements; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; ErbB Receptor Family Protein; ErbB4 gene; Event; Fetal Lung; Goals; Growth; Growth and Development function; Indium; Ligands; Lung; Lung diseases; MAP Kinase Activation Pathway; MAP Kinase Gene; MAP Kinase Signaling Pathways; Mediating; Messenger RNA; Molecular Chaperones; Morbidity - disease rate; Mus; Neuregulins; Nuclear; Nuclear Receptors; Pathway interactions; Phosphorylation; Pregnancy; Premature Birth; Process; Production; Pulmonary Surfactant-Associated Protein B; Receptor Activation; Receptor Signaling; Relative (related person); Respiratory physiology; Role; Signal Transduction; Small Interfering RNA; System; Testing; Transgenic Organisms; Type II Epithelial Receptor Cell; Up-Regulation; cell growth; crosslink; cyclin D2; dimer; fetal; inhibitor/antagonist; insight; lung development; member; monomer; mortality; mutant; novel; novel therapeutics; public health relevance; receptor; research study; respiratory distress syndrome; response; surfactant; trafficking

DESCRIPTION (provided by applicant): Late gestation fetal lung development requires coordinated controls of type 2 cell proliferation and differentiation. While much progress has been made in determining the mechanisms controlling fetal type 2 cell differentiation, relatively little is known about the control of fetal type 2 cell proliferation and the mechanisms which coordinate these two important developmental processes. This proposal is focused on ErbB receptor signaling mechanisms as controlling elements in fetal type 2 cell proliferation. The ErbB receptor family is comprised of four members: the Epidermal Growth Factor Receptor (EGF-R), ErbB2, ErbB3, and ErbB4. Through a system of different ligands and different receptor dimer formation these receptors orchestrate diverse signaling responses to act as important regulators of cell proliferation and differentiation, especially during development. We have shown the importance of this system in type 2 cell differentiation. A paradigm of developmental cell biology is that cell proliferation and differentiation are in mechanistic tension, such that up regulation of one process is associated with down regulation of the other process. In this proposal our hypothesis is that ErbB receptor activation mediates fetal lung type 2 cell growth and differentiation, through diversification of receptor responses. We will address three specific aims: Aim 1: Mechanisms controlling type 2 cell growth versus differentiation are controlled by differential ErbB receptor activity; Aim 2: The mechanisms controlling fetal type 2 cell growth and differentiation utilize ErbB receptor dimers specific to each process; and Aim 3: Determine the role of ErbB receptor nuclear localization in regulating fetal type 2 cell growth and differentiation. New insight into the mechanisms controlling fetal type 2 cell growth will contribute to our ability to develop new therapeutic strategies that will promote normal lung development following preterm birth or other developmental lung diseases. PUBLIC HEALTH RELEVANCE: Premature birth disrupts the growth and development of the lung, especially of specialized lung epithelial cells called type 2 cells, causing significant diseases such as the Respiratory Distress Syndrome and Bronchopulmonary Dysplasia, the leading causes of morbidity and mortality following preterm birth. This project will identify the mechanisms controlling growth and function of immature and mature type 2 cells by studying how ErbB receptor proteins regulate fetal type 2 cell growth and differentiation. The results from this study will provide a platform for developing novel treatments to relieve the burden of RDS and BPD.

描述（由申请方提供）：妊娠晚期胎肺发育需要协调控制2型细胞增殖和分化。虽然在确定控制胎儿2型细胞分化的机制方面取得了很大进展，但对胎儿2型细胞增殖的控制以及协调这两个重要发育过程的机制知之甚少。该建议集中在ErbB受体信号传导机制作为胎儿2型细胞增殖的控制因素。ErbB受体家族由四个成员组成：表皮生长因子受体（EGF-R），ErbB 2，ErbB 3和ErbB 4。通过不同配体和不同受体二聚体形成的系统，这些受体协调不同的信号传导反应，作为细胞增殖和分化的重要调节因子，特别是在发育期间。我们已经证明了该系统在2型细胞分化中的重要性。发育细胞生物学的一个范式是细胞增殖和分化处于机械紧张状态，使得一个过程的上调与另一个过程的下调相关。在这个建议中，我们的假设是，ErbB受体激活介导胎肺2型细胞的生长和分化，通过受体反应的多样化。我们将解决三个具体的目标：目标1：控制2型细胞生长与分化的机制是由不同的ErbB受体活性控制的;目标2：控制胎儿2型细胞生长和分化的机制利用ErbB受体二聚体对每个过程的特异性;目标3：确定ErbB受体核定位在调节胎儿2型细胞生长和分化中的作用。对控制胎儿2型细胞生长的机制的新认识将有助于我们开发新的治疗策略的能力，这些策略将促进早产或其他发育性肺病后的正常肺发育。公共卫生相关性：早产破坏肺的生长和发育，特别是称为2型细胞的特化肺上皮细胞的生长和发育，引起重大疾病，如呼吸窘迫综合征和支气管肺发育不良，这是早产后发病率和死亡率的主要原因。本项目将通过研究ErbB受体蛋白如何调节胎儿2型细胞的生长和分化，确定控制未成熟和成熟2型细胞生长和功能的机制。这项研究的结果将为开发新的治疗方法提供一个平台，以减轻RDS和BPD的负担。