High carbon dioxide impairs lung repair

高二氧化碳会损害肺部修复

• 批准号: 9114654
• 负责人: Ankit Bharat
• 金额: $ 16.21万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114654
• 关键词: 3' Untranslated Regions; Academic Training; Address; Air; Alveolar; Alveolar Macrophages; American; Apoptotic; Area; Award; Basic Science; Binding; Biological Assay; Biology; Bone Marrow; CXCL12 gene; CXCR4 Receptors; Carbon Dioxide; Cells; Cellular biology; Clinical; Clinical Investigator Award; Clinical Research; Clinical Trials; Collaborations; Communities; Complication; Confocal Microscopy; Core Facility; Critical Care; Data; Discipline; Environment; Epithelial; Epithelial Cells; Excision; Faculty; Flow Cytometry; Fostering; Foundations; Functional disorder; Funding; Genetic Transcription; Gifts; Grant; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Healed; Health; Health Care Costs; Hylobates Genus; Hypercapnia; Immunofluorescence Immunologic; Immunology; Impaired wound healing; Injury; Institution; Investigation; Knock-out; Knockout Mice; Knowledge; LIMK1 gene; Laboratories; Laboratory Research; Life; Luciferases; Lung; Lysosomes; Manuscripts; Mediating; Mediator of activation protein; Medicine; Mentors; MicroRNAs; Microscopy; Microsurgery; Modeling; Morbidity - disease rate; Mus; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Phagosomes; Phosphorylation; Physiology; Pleural cavity; Pneumothorax; Positioning Attribute; Postoperative Period; Preparation; Production; Proteins; Pulmonary Emphysema; RNA; Reporter; Research; Research Personnel; Research Training; Resolution; Resources; Risk; Role; Scholarship; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Site; Surface; Surgeon; Techniques; Thoracic Surgical Procedures; Time; Training; Transfection; Transgenic Organisms; Translational Research; Transplantation; United States; Universities; Washington; Work; Wound Healing; abstracting; base; career; cell motility; chemokine; cofilin; experience; healing; human subject; improved; in vivo; inhibitor/antagonist; lung repair; macrophage; meetings; migration; mortality; mouse model; novel; prospective; reconstitution; repaired; research and development; skills; stem; tool; treatment trial; wound

 DESCRIPTION (provided by applicant): Candidate: Dr. Bharat's academic training, research experience and drive place him in an excellent position for a successful career to become a leading independent investigator. He intends to pursue a career in academic surgery with a strong commitment to basic and translational research. He has demonstrated a passion for research as a trainee at Washington University and since his recruitment to Northwestern University. He has already received the prestigious Gibbon Research Scholarship from the American Association of Thoracic Surgery and a Gift of Hope Foundation grant. His lab has generated four abstracts in national meetings and two manuscripts, currently under review, related to the work outlined here. Dr. Bharat completed a prospective clinical trial and took his clinical findings to the laboratory generating strong preliminary data that led to the exciting new hypothesis that forms the basis for this application. These studies have the potential of improving lung healing and outcomes following lung surgery. The K08 program will enable him to expand his research skills by integrating knowledge from inter-related disciplines and become an independent surgeon-scientist, while finding answers to a major clinical problem. Mentors: The Department of Surgery and the Division of Pulmonary and Critical Care Medicine at the Northwestern University are committed to fostering the academic careers of outstanding junior faculty like Dr. Bharat. His mentor Dr. Jacob Sznajder, co-mentors Drs. Harris Perlman and Peter Sporn are well-funded investigators with a long track record of training junior faculty. Thei laboratories have the expertise, tools and resources required to complete the proposed studies. In addition, Dr. Melina Kibbe, surgeon-scientist and Vice Chair for Research and Dr. Malcolm DeCamp, Chief of Thoracic Surgery, are committed to his research development along with the strong institutional support from Northwestern University. Environment: Dr. Bharat will conduct his research training in the Division of Pulmonary and Critical Care Medicine at Northwestern. Strong collaborations between the 13 federally funded investigators in this Division combined with their interactions with Division of Immunology as well as investigators in the Northwestern community and around the world provide an ideal environment for Dr. Bharat to develop into an independent scientist. In addition, the collaboration with the world-class Comprehensive Transplant Center, its state-of-the- art microsurgery center and a number of Northwestern core facilities will facilitate successful conclusion of these studies. The institution has already provided a strong start-up package and protected time to Dr. Bharat. Research: Over 90% of patients undergoing lung surgery will have an air leak from the cut surface of the lung. Removal of apoptotic cells (efferocytosis) at the site of injury and epithelial cell migration is necessaryfor lung repair and resolution of air leaks. Unfortunately up to 50% of patients can demonstrate poor healing that is manifested by prolonged air leak. Prolonged air leak is the major contributor of post-operative mortality after lung surgery. In addition, up to 20% of patients with spontaneous pneumothorax can demonstrate prolonged air leak due to poor lung healing. The pathogenesis of poor lung healing following surgery has not been previously investigated. The studies outlined here originate from our observation in a prospective clinical study of over 120 patients indicating that high concentration of carbon dioxide in the pleural cavity following lung surgery is associated with prolonged air leak. Preliminary data showed that high carbon dioxide suppresses efferocytosis by macrophages as well as epithelial cell migration, leading to delayed wound closure. We propose to investigate the pathways by which hypercarbia suppresses lung repair by the following aims: Aim 1, Determine whether hypercarbia suppresses phagocytosis of apoptotic epithelial cells and CXCL12 production by alveolar macrophages. We will investigate the mechanisms by which hypercarbia suppresses efferocytosis of apoptotic cells by macrophages and production of CXCL12, a chemokine necessary for epithelial cell migration. Aim 2, determine the mechanisms of hypercarbia-induced suppression of Rac1-mediated epithelial cell migration. We will determine how the Rac1-mediated pathway for epithelial cell migration is suppressed by microRNA183 that is upregulated in hypercarbia. Aim 3, Determine whether hypercarbia impairs wound repair in a murine model of epithelial injury. The effects of hypercarbia on macrophages and epithelial cells leading to poor wound healing will be determined using conditional knockout and chimeric mice as well as anti-microRNA (antagomir) therapy.

 应聘者：Bharat博士的学术培训、研究经验和干劲使他在成功的职业生涯中处于有利地位，成为一名领先的独立调查员。他打算从事学术外科的职业生涯，并坚定地致力于基础和翻译研究。他在华盛顿大学实习时和被西北大学录取后，都表现出了对研究的热情。他已经获得了美国胸科外科协会颁发的久负盛名的长臂猿研究奖学金和希望之礼基金会的赠款。他的实验室已经在全国会议上生成了四份摘要和两份手稿，目前正在审查中，与本文概述的工作有关。巴拉特博士完成了一项前瞻性临床试验，并将他的临床发现带到实验室，产生了强大的初步数据，导致了令人兴奋的新 构成这一应用的基础的假设。这些研究有可能改善肺手术后的肺愈合和预后。K08计划将使他能够通过整合相关学科的知识来扩展他的研究技能，并成为一名独立的外科医生兼科学家，同时找到一个重大临床问题的答案。导师：西北大学外科系和肺与重症监护医学部致力于培养像巴拉特博士这样优秀的初级教员的学术生涯。他的导师雅各布·斯纳伊德博士、共同导师哈里斯·珀尔曼博士和彼得·斯波恩博士都是资金雄厚的研究人员，他们在培训初级教员方面有着长期的记录。这些实验室拥有完成拟议研究所需的专业知识、工具和资源。此外，外科科学家兼研究副主席Melina Kibbe博士和胸外科主任Malcolm DeCamp博士在西北大学的大力机构支持下，致力于他的研究开发。环境：巴拉特博士将在西北大学肺部和重症监护医学部进行研究培训。该分部13名联邦资助的研究人员之间的紧密合作，以及他们与免疫学分部以及西北社区和世界各地的研究人员的互动，为巴拉特博士发展成为一名独立科学家提供了理想的环境。此外，与世界一流的综合移植中心、其最先进的显微外科中心和西北大学的一些核心设施的合作将促进这些研究的成功完成。该机构已经为巴拉特博士提供了强有力的启动方案和保障时间。研究：90%以上接受肺部手术的患者会有肺部切割面漏气去除损伤部位的凋亡细胞(胞吐)和上皮细胞迁移是肺修复和解决空气泄漏所必需的。不幸的是，多达50%的患者会表现出愈合不良，表现为长时间的空气泄漏。长时间的漏气是肺部手术后死亡率的主要原因。此外，高达20%的自发性气胸患者可能会因为肺部愈合不良而出现长时间的空气泄漏。手术后肺愈合不良的发病机制以前还没有被研究过。本文概述的研究源于我们对120多名患者的前瞻性临床研究，结果表明，肺部手术后胸腔中高浓度的二氧化碳与长时间的空气泄漏有关。初步数据显示，高二氧化碳抑制巨噬细胞的胞吐作用和上皮细胞的迁移，导致伤口延迟闭合。我们建议通过以下目的来研究高碳酸血症抑制肺修复的途径：目的1，确定高碳酸血症是否抑制肺泡巨噬细胞吞噬凋亡的上皮细胞和产生CXCL12。我们将研究高碳酸血症抑制巨噬细胞对凋亡细胞的吞噬作用和产生CXCL12的机制，CXCL12是上皮细胞迁移所必需的趋化因子。目的2，探讨高碳酸血症抑制Rac1介导的上皮细胞迁移的机制。我们将确定rac1介导的上皮细胞迁移途径是如何被microRNA183抑制的，microRNA183在高碳酸血症中上调。目的3，在小鼠上皮损伤模型中，确定高碳酸血症是否损害创面修复。高碳酸血症对巨噬细胞和上皮细胞的影响将通过条件性基因敲除和嵌合小鼠以及抗microRNA(Antagomir)治疗来确定。