High carbon dioxide impairs lung repair

高二氧化碳会损害肺部修复

• 批准号: 9276767
• 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/9276767
• 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; Health Care Costs; Hylobates Genus; Hypercapnia; Immunofluorescence Immunologic; Immunology; Impaired wound healing; Impairment; Injury; Institution; Investigation; Knock-out; Knockout Mice; Knowledge; LIMK1 gene; Laboratories; Laboratory Research; 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; Recruitment Activity; 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; career; cell motility; chemokine; cofilin; experience; healing; human subject; improved; in vivo; inhibitor/antagonist; lung repair; macrophage; meetings; migration; mortality; mouse model; novel; prospective; public health relevance; reconstitution; repaired; research and development; skills; stem; tool; treatment trial; wound closure

 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.

 描述（由申请人提供）：候选人：巴拉特博士的学术培训，研究经验和驱动器放置在一个成功的职业生涯，成为一个领先的独立调查员他一个很好的位置。他打算从事学术手术的职业生涯，并坚定地致力于基础和转化研究。作为华盛顿大学的实习生，以及被西北大学录取后，他表现出了对研究的热情。他已经获得了美国胸外科协会颁发的久负盛名的Giovanni研究奖学金和希望基金会的赠款。他的实验室已经在国家会议上产生了四个摘要和两个手稿，目前正在审查中，与这里概述的工作有关。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，产生了强有力的初步数据，导致了令人兴奋的新发现。 这一假设构成了本申请的基础。这些研究有可能改善肺手术后的肺愈合和结局。K 08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-科学家，同时找到重大临床问题的答案。导师：西北大学的外科系和肺部和重症监护医学部致力于培养像巴拉特博士这样的优秀初级教师的学术生涯。他的导师Jacob Sznajder博士、共同导师Harris Perlman博士和Peter Sporn博士都是资金充足的调查人员，在培训初级教师方面有着长期的记录。他们的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，Melina Kibbe博士，外科医生，科学家和研究副主席和Malcolm DeCamp博士，胸外科主任，致力于他的研究发展沿着来自西北大学的强有力的机构支持。环境：巴拉特博士将在西北大学的肺部和重症监护医学部进行研究培训。该部门13名联邦资助的研究人员之间的密切合作，加上他们与免疫学部门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一些西北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一个强大的启动包和保护时间。研究：超过90%的接受肺部手术的患者会从肺部的切割表面漏气。清除损伤部位的凋亡细胞和上皮细胞迁移对于肺修复和解决漏气是必要的。不幸的是，高达50%的患者可以表现出愈合不良，表现为长时间的漏气。长期漏气是肺部手术后术后死亡率的主要原因。此外，高达20%的自发性气胸患者可因肺部愈合不良而出现长期漏气。手术后肺愈合不良的发病机制以前尚未研究。本文概述的研究源于我们在一项对120多名患者进行的前瞻性临床研究中的观察结果，该研究表明肺手术后胸膜腔中的高浓度二氧化碳与长期漏气相关。初步数据显示，高二氧化碳抑制巨噬细胞的红细胞增多以及上皮细胞迁移，导致伤口闭合延迟。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凋亡上皮细胞的吞噬作用和肺泡巨噬细胞产生CXCL 12。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上皮细胞迁移所必需的趋化因子CXCL 12的产生的机制。目的2探讨高碳酸血症抑制Rac 1介导的上皮细胞迁移的机制。我们将确定Rac 1介导的上皮细胞迁移途径是如何被高碳酸血症中上调的microRNA 183抑制的。目的3，在上皮损伤的小鼠模型中确定高碳酸血症是否损害伤口修复。高碳酸血症对巨噬细胞和上皮细胞的影响导致伤口愈合不良，将使用条件性敲除和嵌合小鼠以及抗microRNA（莫洛莫）治疗来确定。