Role of Rb/p16 pathway in Pulmonary Progenitor Cell Regulation

Rb/p16 通路在肺祖细胞调节中的作用

• 批准号: 8098942
• 负责人: David Scott Simpson
• 金额: $ 4.11万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2012-06-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098942
• 关键词: Ablation; Adult; Age; Alveolus; American; Apoptosis; Asthma; Breeding; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cellular Stress; Cessation of life; Chronic Obstructive Airway Disease; Chronic lung disease; Data; Development; Disease; Distal; Elderly; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Event; Figs - dietary; Financial compensation; Goals; Growth; Hyperplasia; Injury; Lead; Lung; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Natural regeneration; Newborn Infant; Organ; Pathway interactions; Phosphorylation; Physiological; Play; Prevention; Proteins; Regulation; Regulatory Pathway; Respiratory physiology; Risk; Role; Stem cells; Stimulus; Stress; Testing; Type II Epithelial Receptor Cell; Up-Regulation; Work; Wound Healing; base; cell growth; design; disease diagnosis; improved; in vivo; injury and repair; insight; lung injury; mortality; mouse model; novel; novel strategies; public health relevance; repaired; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Chronic lung diseases such as asthma and chronic obstructive pulmonary disease are associated with continual injury and repair. Epithelial regeneration after injury is a key component in restoring lung function, and requires the coordinate regulation of progenitor cell proliferation, survival and differentiation. Type II cells serve as epithelial progenitor cells and play a crucial role in epithelial repair after injury. The long-term objective of the present work is to elucidate the molecular mechanisms governing epithelial remodeling in chronic lung disease with the goal of developing novel approaches to disease diagnosis, treatment and prevention. The central hypothesis is that Rb and pl6 act as distinct and critical regulators of type II cell proliferation and survival. Preliminary data demonstrate age and Rb dependent pl6 induction in lung epithelial progenitor cells in vivo, and provide evidence that Rb and pl6 regulate type II cell growth. Aim one in this proposal is designed to determine critical Rb and pl6 functions essential in regulating type II progenitor cell growth in culture. Cellular proliferation and survival will be assessed in Rb, pl6 and Rb/pl6 deficient primary type II cultures obtained from murine lungs wherein Rb ablation is targeted to the lung epithelium in apl6 proficient or null background. Results will be compared to wild type controls to determine unique and overlapping Rb and pl6 functions. The second aim will elucidate the physiologic role of pl6 induction on lung epithelial cell growth in vivo. Effects of combined Rb and pl6 loss on lung morphogenesis, cell proliferation and cell survival will be assessed and compared to wild type as well as Rb or pl6 deficient lungs. These studies will directly determine the physiologic relevance of pl6 induction in vivo and elucidate molecular mechanisms underlying pl6 function in pulmonary progenitor cells in vivo. Completion of this work will result in novel insights into regulatory pathways governing lung epithelial regeneration by identifying key molecular mediators of pulmonary epithelial cell growth and survival. Public Health Relevance: More than 35 million Americans suffer from chronic lung diseases that cause significant morbidity and mortality. The Rb/pl6 pathway plays a fundamental role in regulating cell growth, differentiation and survival. This proposal aims to elucidate Rb and pl6 dependent mechanisms controlling lung epithelial progenitor cell growth. These studies are expected to improve understanding of the molecular and physiological basis of disease thereby facilitating development of novel approaches to treatment.

描述（由申请人提供）：慢性肺病，例如哮喘和慢性阻塞性肺病，与持续损伤和修复有关。损伤后上皮再生是肺功能恢复的关键组成部分，需要祖细胞增殖、存活和分化的协调调节。 II型细胞作为上皮祖细胞，在损伤后的上皮修复中发挥着至关重要的作用。目前工作的长期目标是阐明控制慢性肺病上皮重塑的分子机制，目标是开发疾病诊断、治疗和预防的新方法。中心假设是Rb和p16作为II型细胞增殖和存活的独特且关键的调节剂。初步数据证明体内肺上皮祖细胞中年龄和Rb依赖性p16诱导，并提供Rb和p16调节II型细胞生长的证据。该提案的目标之一是确定在调节培养物中II型祖细胞生长中必需的关键Rb和p16功能。将在从鼠肺获得的Rb、p16和Rb/p16缺陷的原代II型培养物中评估细胞增殖和存活，其中Rb消融靶向ap16熟练或无效背景中的肺上皮。将结果与野生型对照进行比较以确定独特且重叠的Rb和p16功能。第二个目标将阐明pl6诱导对体内肺上皮细胞生长的生理作用。将评估Rb和p16联合缺失对肺形态发生、细胞增殖和细胞存活的影响，并与野生型以及Rb或p16缺陷型肺进行比较。这些研究将直接确定体内pl6诱导的生理相关性，并阐明体内肺祖细胞中pl6功能的分子机制。这项工作的完成将通过识别肺上皮细胞生长和存活的关键分子介质，对控制肺上皮再生的调控途径产生新的见解。 公共卫生相关性：超过 3500 万美国人患有慢性肺部疾病，导致高发病率和死亡率。 Rb/p16途径在调节细胞生长、分化和存活中发挥重要作用。该提案旨在阐明控制肺上皮祖细胞生长的Rb和pl6依赖性机制。这些研究有望增进对疾病的分子和生理学基础的理解，从而促进新治疗方法的开发。