Mechanisms of sex specific differences in neonatal hyperoxic lung injury

新生儿高氧性肺损伤的性别差异机制

• 批准号: 9052817
• 负责人: Krithika Lingappan
• 金额: $ 15.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052817
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Advisory Committees; Air; Alveolar; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Area; Attenuated; Award; Basic Science; Bioinformatics; Biometry; Birth; Blood Vessels; Bronchopulmonary Dysplasia; C57BL/6 Mouse; CYP1A1 gene; Clinical; Cytochrome P450; Cytochromes; Data; Development; Diagnosis; Disease; Doctor of Medicine; Doctor of Philosophy; Environment; Enzymes; Exposure to; Female; Flutamide; Funding; Gender; Genes; Goals; Gonadal Steroid Hormones; Health; Human; Hyperoxia; Impairment; Incidence; Inflammation; Injury; Investigation; Knockout Mice; Knowledge; Lead; Lung; Lung diseases; Manuscripts; Measurement; Measures; Mediating; Medical center; Medicine; Mentors; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Neonatal; Neonatology; Outcome; Oxidative Stress; Oxygen; Pathway interactions; Pediatrics; Peer Review; Phase; Physicians; Play; Premature Birth; Preparation; Prevention; Protein Array; Protein Family; Protein Isoforms; Proteome; Publications; Pulmonary Pathology; Reactive Oxygen Species; Reading; Research; Research Design; Research Personnel; Research Training; Resistance; Resources; Role; Safe Sex; Scientist; Sex Characteristics; Signaling Protein; System; Systems Biology; TNFRSF5 gene; Techniques; Testing; Testosterone; Testosterone Propionate; Texas; Therapeutic; Time; Training; Training Programs; United States; Vascularization; Wild Type Mouse; Work; base; career; career development; college; experience; humanized mouse; improved; innovation; lung development; lung injury; lung maturation; male; meetings; mouse model; neonatal lung injury; neonatal outcome; new therapeutic target; novel strategies; perinatal medicine; postnatal; premature neonates; prevent; professor; programs; research and development; sex; sexual dimorphism; skills; tenure track; training opportunity; transcriptome

 DESCRIPTION (provided by applicant): This K08 proposal describes a five-year research and training plan that will facilitate the transition of Krithika Lingappan, M.D., to an independent academic researcher in the field of neonatal lung injury. Dr. Lingappan has a strong background in basic science, and completed her training in neonatology at Baylor College of Medicine (BCM), where she is now a tenure-track assistant professor. Her overarching research goal is to delineate the mechanisms of sex-specific differences in neonatal hyperoxic lung injury. Dr. Lingappan is working towards a Ph.D. degree in BCM's Clinical Scientist Training Program. Her primary mentor is Bhagavatula Moorthy, Ph.D., Professor of Pediatrics at BCM, who is a well-funded researcher in the field of hyperoxic lung injury, ARDS and cytochrome P450 and has a highly successful track record of mentoring. She has also assembled an advisory committee of four outstanding translational researchers to aid in her research and career development. Dr. Lingappan has taken biostatistics and research design courses and completed preliminary studies. She will take additional courses relevant to her career goal and research plan, with the understanding that completion of the research aims will require intimate knowledge of 1) manipulation of mouse models of experimental bronchopulmonary dysplasia and assessment of lung injury and lung development; 2) established and emerging techniques in molecular biology; 3) bioinformatics and systems biology approach to diseases; and 4) sex/gender oriented research. Dr. Lingappan's immediate goals are to: 1) Improve her knowledge and acquire new skills in the area of neonatal hyperoxic lung injury. 2) Develop skill sets in bioinformatics and systems biology approach to diseases. 3) Build on her knowledge of the role of cytochrome P450 system and investigate its role in sex- specific differences in neonatal hyperoxic lung injury. 4) Develop a deeper understanding of sex-hormone dependent and independent mechanisms responsible for sexual dimorphism in neonatal outcomes. 5) Generate data leading to peer reviewed publications and presentations in national meetings and to prepare a strong, hypothesis-driven proposal to study the specific genes and pathways responsible for sexual dimorphism in bronchopulmonary dysplasia, leading to an R01 application. The long-term goal is to attain the skills, knowledge and experience needed to become a successful academic physician-scientist with independent research and funding in the area of neonatal hyperoxic lung injury and mechanisms behind sex- specific outcomes in neonatal-perinatal medicine. The training opportunities and resources at Baylor College of Medicine, in the world-renowned Texas Medical Center in Houston, provide an ideal environment for Dr. Lingappan's career development program. She will continue to have at least 75% protected time to devote to the activities described in this proposal. Her training and research plan incorporate a combination of coursework, directed reading, mentoring, hands-on research experience, presentations at national and regional scientific meetings, preparation of manuscripts and an R01 application. Research: Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia. The cytochrome P450 (CYP)1A family of proteins are protective against hyperoxic lung injury, and sex-specific differences in the expression of CYP1A are known under hyperoxia, with higher levels in females. Androgens are known to delay lung maturation and are detrimental in acute lung injury animal models. The reasons underlying sexually dimorphic outcomes in premature neonates are not known, and a focused investigation of the effect of sex/gender on hyperoxic lung injury and the underlying mechanisms has not been attempted. The specific aims of the project are to: 1. compare lung injury between male and female neonatal mice after postnatal hyperoxia exposure and elucidate the underlying molecular mechanism(s), 2. determine the mechanistic role of cytochrome P50 1A enzymes in the sex-specific differences in neonatal hyperoxic lung injury, and 3. elucidate the effect of androgens on sex-specific differences in neonatal hyperoxic lung injury. Understanding the basis of the sex-based differences is important in order to develop new approaches and individualized therapeutic options for the prevention, diagnosis, and treatment of BPD. The research described in this proposal is innovative, feasible to be completed within the award period, and of high potential significance. This research will be a substantive addition to the knowledge gap and will advance the field of neonatal hyperoxic lung injury and will serve as a vehicle for the advancement of Dr. Lingappan's career as an independent investigator.

 描述（由申请人提供）：本K08提案描述了一项为期五年的研究和培训计划，该计划将促进Krithika Lingappan，M.D.，新生儿肺损伤领域的独立学术研究者。Lingappan博士在基础科学方面有很强的背景，并在贝勒医学院（Baylor College of Medicine）完成了她的口腔医学培训，她现在是那里的终身助理教授。她的首要研究目标是描绘新生儿高氧肺损伤的性别特异性差异的机制。林伽潘博士正在攻读博士学位。临床科学家培训计划。她的主要导师是Bhagavatula Moorthy博士，儿科教授，他是高氧肺损伤，ARDS和细胞色素P450领域的资金充足的研究人员，并有非常成功的指导记录。她还组建了一个由四位杰出的翻译研究人员组成的咨询委员会，以帮助她的研究和职业发展。Lingappan博士参加了生物统计学和研究设计课程，并完成了初步研究。她将参加与她的职业目标和研究计划相关的其他课程，并了解完成研究目标将需要熟悉以下知识：1）实验性支气管肺发育不良小鼠模型的操作和肺损伤和肺发育的评估; 2）分子生物学中的成熟和新兴技术; 3）疾病的生物信息学和系统生物学方法;（4）性/性别导向的研究。Lingappan博士的近期目标是：1）提高她在新生儿高氧肺损伤领域的知识并获得新技能。2)发展生物信息学和系统生物学方法治疗疾病的技能。3)基于她对细胞色素P450系统作用的认识，研究其在新生儿高氧肺损伤性别特异性差异中的作用。4)发展性激素依赖性和独立的机制，负责新生儿结局的性二型性的更深入的理解。5)生成导致同行评审的出版物和国家会议上的演示文稿的数据，并准备一个强有力的，假设驱动的建议，以研究负责支气管肺发育不良性二型性的特定基因和途径，导致R01应用。长期目标是获得所需的技能，知识和经验，成为一个成功的学术医生，科学家与独立的研究和资金在新生儿高氧肺损伤和机制背后的性别特异性结果在围产期医学领域。贝勒医学院的培训机会和资源，在世界著名的得克萨斯州医学中心在休斯顿，为林加潘博士的职业发展计划提供了一个理想的环境。她将继续有至少75%的受保护时间用于本提案中所述的活动。她的培训和研究计划包括课程作业，定向阅读，指导，实践研究经验，在国家和区域科学会议上的演讲，手稿的准备和R01应用程序的组合。研究：男性被认为是支气管肺发育不良的独立预测因素。细胞色素P450（CYP1A）1A蛋白家族对高氧肺损伤具有保护作用，并且已知在高氧下CYP1A表达的性别特异性差异，女性中的水平较高。已知雄激素延迟肺成熟，并且在急性肺损伤动物模型中是有害的。早产儿性别二态性结局的潜在原因尚不清楚，尚未尝试对性别/性别对高氧肺损伤的影响及其潜在机制进行重点调查。该项目的具体目标是：1.比较出生后高氧暴露对雄性和雌性新生小鼠肺损伤的差异，并阐明其分子机制。确定细胞色素P50 1A酶在新生儿高氧肺损伤性别特异性差异中的机制作用; 3.阐明雄激素对新生儿高氧肺损伤性别特异性差异的影响。了解基于性别的差异的基础是重要的，以便开发新的方法和个性化的治疗选择，预防，诊断和治疗BPD。本建议书所述的研究具有创新性，在奖励期内完成可行，具有很高的潜在意义。这项研究将是对知识差距的实质性补充，并将推动新生儿高氧肺损伤领域的发展，并将作为推动Lingappan博士作为独立研究者的职业生涯的工具。