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.

Public Health Relevance

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. Understanding the molecular basis of sex-specific differences, as proposed in this application, will lead to the development of novel approaches and individualized therapeutic options for BPD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
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Colombini-Hatch, Sandra
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Baylor College of Medicine
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Veith, Alex C; Bou Aram, Boura'a; Jiang, Weiwu et al. (2018) Mice Lacking the Cytochrome P450 1B1 Gene Are Less Susceptible to Hyperoxic Lung Injury Than Wild Type. Toxicol Sci 165:462-474
Lingappan, Krithika (2018) NF-?B in Oxidative Stress. Curr Opin Toxicol 7:81-86
Lingappan, Krithika; Maturu, Paramahamsa; Liang, Yanhong Wei et al. (2018) ?-Naphthoflavone treatment attenuates neonatal hyperoxic lung injury in wild type and Cyp1a2-knockout mice. Toxicol Appl Pharmacol 339:133-142
Jiang, Weiwu; Maturu, Paramahamsa; Liang, Yanhong Wei et al. (2018) Hyperoxia-mediated transcriptional activation of cytochrome P4501A1 (CYP1A1) and decreased susceptibility to oxygen-mediated lung injury in newborn mice. Biochem Biophys Res Commun 495:408-413
Borza, Corina M; Pozzi, Ambra; Plosa, Erin J (2018) Discoidin Domain Receptor 2, a Potential Therapeutic Target in Lung Fibrosis. Am J Respir Cell Mol Biol 59:277-278
Maturu, Paramahamsa; Wei-Liang, Yanhong; Jiang, Weiwu et al. (2017) Newborn Mice Lacking the Gene for Cyp1a1 Are More Susceptible to Oxygen-Mediated Lung Injury, and Are Rescued by Postnatal ?-Naphthoflavone Administration: Implications for Bronchopulmonary Dysplasia in Premature Infants. Toxicol Sci 157:260-271
Coarfa, Cristian; Zhang, Yuhao; Maity, Suman et al. (2017) Sexual dimorphism of the pulmonary transcriptome in neonatal hyperoxic lung injury: identification of angiogenesis as a key pathway. Am J Physiol Lung Cell Mol Physiol 313:L991-L1005
Zhang, Yuhao; Lingappan, Krithika (2017) Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells. Biochem Biophys Res Commun 486:431-437
Lingappan, Krithika; Maity, Suman; Jiang, Weiwu et al. (2017) Role of Cytochrome P450 (CYP)1A in Hyperoxic Lung Injury: Analysis of the Transcriptome and Proteome. Sci Rep 7:642
Zhang, Yuhao; Jiang, Weiwu; Wang, Lihua et al. (2017) Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro: Role of Hif-1?. Toxicol Appl Pharmacol 332:8-14

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