Affiliation: Institute for Biogenesis Research Department of Anatomy, Biochemistry and Physiology John A. Burns School of Medicine University of Hawaii
Graduate Faculty: Developmental and Reproductive Biology (DRB) Cell and Molecular Biology (CMB)
Phone: (808) 956-7417
Fax: (808) 956-7316
Email: johann@hawaii.edu
Address: IBR, 1960 East-West Rd., Room E112, Honolulu, HI 96822
Development of non-viral transposase-based vectors for gene therapy Transgenesis
Impact of maternal and paternal obesity on adult onset metabolic disease for subsequent generations
Description Of Research
Impact of maternal obesity on fetal development andgrowth and health later in life
In recent decades, the increase in obesity, particularly in industrialized countries has taken on epidemic proportions. For example, in the US alone, 40% of adults 20 years old and over are obese. An even higher prevalence of obesity exists for minority populations where obesity rates for Native Hawaiians and other Pacific Islanders are 2-3 times higher than the general population.
Maternal overweight and obesity are associated with perturbations in fetal growth leading to poor neonatal outcomes and furthermore long-term consequences for offspring health and wellbeing. Molecular mechanisms mediating the effects of disturbances in maternal nutrition during pregnancy on fetal growth and health later in life have yet to be fully elucidated.
The placenta serves as an interface between the fetal and maternal circulation and one of its key functions is to supply nutrients to the fetus. As the quantity of nutrients available to the fetus is a significant determinant of fetal growth, the placenta has been implicated in fetal growth and development. The mechanisms linking in utero nutrient excess, fetal overgrowth and disease development later in life are poorly understood and are thought to include alterations in placental nutrient transport.
Most pregnancy complications, including maternal obesity, IUGR, preeclampsia and stillbirth, are caused by changes in placental development and function. The syncytiotrophoblast is directly exposed to maternal blood in the intervillous space and therefore highly accessible to drugs or other therapeutic agents in the maternal circulation. This represents a tremendous opportunity for targeted intervention strategies and provides a strong rationale for targeting the placenta with the ultimate goal of improving fetal outcomes in common pregnancy complications. Additionally, the placenta is a tissue with a finite life span, essential for fetal development but discarded after birth, it is well suited for improving fetal wellbeing through genetic modifications, without causing problems associated with gene transfer directly into the host genome.
We have developed a strategy for achieving a placenta-specific modulation in nutrient transporter gene expression. Our intention is to decrease the glucose transport into the placenta in vivo in a maternal adiposity mouse model and evaluate if this approach will attenuate fetal overgrowth and subsequent metabolic syndrome in offspring. We will deliver this vector in a tissue specific manner in vivo by utilizing sonoporation, an innovative approach for gene transfer that combines very high tissue specificity with minimally invasive delivery. This approach may be adaptable to the human placenta in the future, and thus may represent a novel early intervention strategy for IUGR pregnancies.
Selected Publications
Elston M, Urschitz J. Transposase-mediated gene modulation in the placenta. Placenta. 2017;59 Suppl 1:S32-S6. Epub 2017/08/06. doi: 10.1016/j.placenta.2017.07.016. PubMed PMID: 28778732; PMCID: PMC5682209.
Anderson CD, Urschitz J, Khemmani M, Owens JB, Moisyadi S, Shohet RV, Walton CB. Ultrasound directs a transposase system for durable hepatic gene delivery in mice. Ultrasound Med Biol. 2013;39(12):2351-61. Epub 2013/09/17. doi: 10.1016/j.ultrasmedbio.2013.07.002. PubMed PMID: 24035623; PMCID: PMC3838570.
Owens JB, Urschitz J, Stoytchev I, Dang NC, Stoytcheva Z, Belcaid M, Maragathavally KJ, Coates CJ, Segal DJ, Moisyadi S. Chimeric piggyBac transposases for genomic targeting in human cells. Nucleic acids research. 2012; 40(14):6978-91. Epub 2012/04/12. doi: 10.1093/nar/gks309. PubMed PMID: 22492708; PMCID: PMC3413120.
Urschitz J, Kawasumi M, Owens J, Morozumi K, Yamashiro H, Stoytchev I, Marh J, Dee JA, Kawamoto K, Coates CJ, Kaminski JM, Pelczar P, Yanagimachi R, Moisyadi S. Helper-independent piggyBac plasmids for gene delivery approaches: strategies for avoiding potential genotoxic effects. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(18):8117-22. Epub 2010/04/21. doi: 10.1073/pnas.1003674107. PubMed PMID: 20404201; PMCID: PMC2889585.
Brizzolara SS, Killeen J, Urschitz J. Gene expression profile in pelvic organ prolapse. Molecular human reproduction. 2009;15(1):59-67. Epub 2008/12/06. doi: 10.1093/molehr/gan074. PubMed PMID: 19056808; PMCID: PMC2639232.