This application is in response to NHLBI TOSI HL-131: Exposure of the developing lung to cigarette smoke is an independent risk factor for the development of chronic lung disease (CLD), including asthma in later life. Even more importantly, recently, it has been shown that by altering specific developmental signaling pathways necessary for fetal lung development, the perinatal nicotine exposure-related CLD risk is not restricted only to the nicotine exposed offspring, but is also transmitted transgenerationally to the progeny of the subsequent non-exposed offspring (Rehan et al, AJP Lung; 2013;305:L501-7). Specifically, nicotine alters the normal differentiation of mesenchymal cells in the developing lung by stimulating the Wnt pathway, inhibiting PPAR? signaling, resulting in the myogenic phenotype of the airway smooth muscle (ASM) cells. Interestingly, these effects are sex-specific, with the molecular and functional effects on ASM cells seen exclusively in males. Importantly, PPAR? agonists, which are potent Wnt antagonists, can inhibit and/or reverse these effects. Hypothesizing that these effects are determined by nicotine-induced epigenetic changes in the gonadal germ line, which lead to lung specific molecular and functional effects, we propose to examine the mechanistic basis for the 1) transgenerational (TG) transmission, and 2) gender-specificity of perinatal nicotine exposure-induced offspring lung hyperresponsive phenotype.
In Aim 1, we will determine whether the perinatal nicotine exposure-induced lung phenotype is transmitted via the male vs. female germline (Aim 1A), whether it is affected by the genetic diversity of parents (Aim 1B), and whether the lung phenotype seen in childhood is also seen in adulthood (Aim 1C).
In Aim 2, we will determine whether the more pronounced perinatal nicotine exposure-induced pulmonary phenotype seen in males is determined by the differential PKC expression and activation in ASM cells of males vs. females (Aim 2A) and whether this is abrogated by blocking the specific PKC isoform involved (Aim 2B).
In Aim 3, we will determine whether perinatal nicotine exposure-induced germ line and ASM epigenetic changes are transmitted from F1 to F3 generation (Aim 3A) and whether concomitant suppression of nicotine-induced Wnt activation, using PPAR? agonist rosiglitazone, blocks these epigenetic changes and protects against perinatal nicotine-induced TG transmission of the lung myogenic phenotype (Aim 3B). The concepts put forward in this proposal are totally novel and innovative, thus advancing the field significantly by addressing the fundamental mechanism(s) that explain the detrimental effects of maternal smoking not only on the exposed offspring, but also on the many generations that follow. Using this comprehensive cell-molecular-epigenetic approach, the proposed studies are likely to not only generate new, pivotal molecular data that could significantly impact our understanding of the pathogenesis of CLD, but also provide novel mechanistic information underlying CLD risk, paving the way for studying molecular mechanisms underlying TG effects on a host of other environmental exposures.

Public Health Relevance

Chronic lung disease, including childhood asthma, is a major public health problem worldwide with maternal smoking during pregnancy is a significant contributor to this ever growing epidemic. Additionally, there is emerging evidence for the transgenerational transmission of asthma and other lung disease-related risks following exposure to maternal smoke during pregnancy. The studies proposed in this application aim to discover the molecular basis underlying the increased predisposition to such lung diseases in future generations, provide fundamental molecular insights to the development of childhood asthma, and help devise new treatments for many chronic lung diseases including childhood asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127237-04
Application #
9640471
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Natarajan, Aruna R
Project Start
2016-02-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Sakurai, Reiko; Liu, Jie; Wang, Ying et al. (2018) Prevention of perinatal nicotine-induced bone marrow mesenchymal stem cell myofibroblast differentiation by augmenting the lipofibroblast phenotype. Clin Sci (Lond) 132:2357-2368
Hwang, Jung S; Rehan, Virender K (2018) Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology, Prevention, and Treatment. Lung 196:129-138
Liu, Yitian; Ji, Bo; Zhao, Guozhen et al. (2018) Protective effect of electro-acupuncture at maternal different points on perinatal nicotine exposure-induced pulmonary dysplasia in offspring based on HPA axis and signal transduction pathway. Biochem Biophys Res Commun 505:586-592
Chuang, Tsai-Der; Sakurai, Reiko; Gong, Ming et al. (2018) Role of miR-29 in Mediating Offspring Lung Phenotype in a Rodent Model of Intrauterine Growth Restriction. Am J Physiol Regul Integr Comp Physiol :
Sakurai, Reiko; Lee, Cindy; Shen, Humphrey et al. (2018) A Combination of the Aerosolized PPAR-? Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats. Neonatology 113:296-304
Ji, Bo; Zhao, Guo-Zhen; Sakurai, Reiko et al. (2016) Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Lung Phenotype in Offspring. Lung 194:535-46
Sakurai, Reiko; Liu, Jie; Gong, Ming et al. (2016) Perinatal nicotine exposure induces myogenic differentiation, but not epithelial-mesenchymal transition in rat offspring lung. Pediatr Pulmonol 51:1142-1150
Taylor, Sneha K; Sakurai, Reiko; Sakurai, Tokusho et al. (2016) Inhaled Vitamin D: A Novel Strategy to Enhance Neonatal Lung Maturation. Lung 194:931-943
Gong, Ming; Antony, Sahaya; Sakurai, Reiko et al. (2016) Bone marrow mesenchymal stem cells of the intrauterine growth-restricted rat offspring exhibit enhanced adipogenic phenotype. Int J Obes (Lond) 40:1768-1775
Cannon, Daniel T; Liu, Jie; Sakurai, Reiko et al. (2016) Impaired Lung Mitochondrial Respiration Following Perinatal Nicotine Exposure in Rats. Lung 194:325-8

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