In considering how best to mitigate neonatal morbidity and mortality, we embarked on an exploratory line of research in preterm labor wherein our expertise in vascular biology, smooth muscle and ion channel physiology might be leveraged to address abnormal uterine contractility. Thus, over the past 5 years, we have became increasingly focused upon uterine contractility. Important discoveries in this area include identification an ion channel, transient receptor potential vanilloid 4, that plays a central and critical role in the control of uterine tone during both quiescence and activation. Our laboratory has created multiple experimental models, established collaborations, and acquired reagents (specifically genetically modified mice) that allow us to rigorously and mechanistically probe the cellular and molecular underpinnings of both physiologic and pathophysiologic labor. We are poised to build upon our recent findings with a team of scientists and clinicians to create new knowledge and consider how best to move the discoveries from bench to bedside.
Researchers: Judith Ingles, Lihua Ying, Zahidee Rodriguez, David N. Cornfield
Preterm birth is a major health epidemic that kills around one million babies and effects approximately 15 million births each year. Inflammation is the only known pathology with substantial evidence of causality for both spontaneous term and preterm labor. The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective calcium permeable cation channel, that has recently been demonstrated to promote inflammatory signaling through the activation NFkB and upregulation of multiple pro-inflammatory cytokines in adipose tissue and lung epithelial cells. Thus, this project investigates the role of TRPV4 in the regulation of uterine inflammation and the subsequent molecular processes that lead to the onset of contraction, both in the context of term and preterm labor. Our laboratory hopes that a more concrete understanding of the physiological processes of labor will lead to the development of powerful anti-contractile or tocolytic therapies and thus the eradication of preterm birth.
David N. Cornfield, M.D.
Judith Ingles, Ph.D.
Zahidee Rodriguez, M.D.
Lihua Ying, Ph.D.
- Ying L,, Becard M, Lyell D, Han X, Shortliffe L, Husted CI, Alvira CM, Cornfield DN. Sci Transl Med. 2015 7(319):319ra204. The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy.
- Ying L ,Alvir CM, Cornfield DN. Am J Physiol Lung Cell Mol Physiol. 2018 315(1):L66-L77 Developmental differences in focal adhesion kinase expression modulate pulmonary endothelial barrier function in response to inflammation.
- Mahapatra S, Ying L, Ho PP, Kurnellas M. Rothbard J, Steinman L and Cornfield DN. PLoS One 2018 Jul 10;13(7):e0199206. An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis.
- Chia Wang, Lihua Ying, Elizabeth A. Barnes, Eloa S. Adams, Francis Y. Kim, Karl W. Engel, Cristina M. Alvira and David N. Cornfield Am J Physiol Lung Cell Mol Physiol 315: L422–L431, 2018 Pulmonary artery smooth muscle cell HIF-1regulates endothelin expressionvia microRNA-543.
- Kim YM, Barnes EA, Alvira CM, Ying L, Reddy S, Cornfield DN. Circ Res. 2013 Apr 26;112(9):1230-3. Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation.
- Alvira CM, Umesh A, Husted C, Ying L, Hou Y, Lyu SC, Nowak J, Cornfield DN. Am J Respir Cell Mol Biol. 2012 Nov;47(5):669-78. Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production.