Bird Research Team
I trained as Medical Biochemist, and then undertook two highly successful postdoctoral fellowships focused on cell signaling and molecular endocrinology at the level of adrenal steroid biosynthesis and its relationship to zone specific cell signaling as it impacts upon P450/HSD gene expression. This lead to an interest in the analysis of circulating steroids as an indicator of normal vs incomplete development, and as an indicator of normal vs prolonged stress. As a result of my move to an ObGyn department I then applied my knowledge to the investigation of changes in vascular function during pregnancy, I identified for the first time that pregnancy induced adaptation of endothelial function occurs through adaptive programming of cell signaling. Since pioneering the first use of endothelial cell primary culture models (1996) to identify this adaptive programming of cell signaling in response to pregnancy, this laboratory has also gained the unique expertise to image simultaneous real time cell imaging of Ca2+ and NO. The most important recent advance has been the realization that the mechanistic basis for adaptation and failure of adaptation in humans is mediated at the level of Cx43 through the growth factors and cytokines of wounding that are also seen in preeclampsia. My more recent collaboration with Dr Dinesh Shah (Former Head MFM Division) has also allowed the realization of a joint goal to undertake more translational studies in this area to extend our observation from sheep to diseases of human pregnancy, namely preeclampsia. The specific goal of a recently completed R21 investigation was the validation of the UV Endo preparation and associated HUVEC cell model as a suitable basis for study of pregnancy adapted function at the level of Ca2+ signaling and associated NO production and its corresponding failure in PE subjects, and that is a part of what drives this application. In addition, we have recently partnered with Oliver Wieben and his colleagues from Radiology and Medical Physics in the first application of MRI to study human pregnancy (U01 Parent Application) at the level of blood flow, blood oxygenation, and placental perfusion. Beyond my research interests, I also have taken on a leadership role in research and training nationally as well as on campus. I mentor trainees through junior faculty in research and grant writing at the Society Reproductive Investigation and Perinatal Research Society. On campus I serve as Vice Chair in the dept ObGyn, and I am Director of both the Endocrinology and Reproductive Physiology Training Program and the Integrated Program in Endocrinology. I personally train from Predoctoral PhD through faculty on traditional tenure and clinical tracks. I am PI of a Predoctoral T32 (ERP - funded 4 cycles), CoI on an R25 Bridges award to Molly Carnes, CoI of a Health Disparities T32 led by Deb Ehrenthal, and I chair the ObGyn dept committee of tenured professors that works with the Chairs office to guide those undergoing promotions. I lead two RCR courses on campus aimed at trainees from predoc (ObGyn955) through faculty K applicants (ObGyn956). In 2018 I was awarded the Doris Schlesinger award for excellence in mentoring of women faculty.
Advanced MRI For Uteroplacental Flow, Perfusion, Oxygenation & Inflammation (Shah and Weiben PI, Bird CoI/Alternate PI)
Start Date: 10/1/2015 --- End Date: 9/30/2020
Sponsor: NIH/NICHD U01 HD087216
The purpose of this award is to deveope new MRI imaging methodologies for the monitoring of normal blood flow, oxygenation and immune cell location in the human placenta in early pregnancy and follow those changes to term.
Importance of Endothelial Cell-Cell Communication at the Maternal Fetal Interface test
Start Date: 8/15/2013 --- End Date: 6/30/2019
Sponsor: NIH P01 HD038843- (Bird-PI)
This proposal studies cell cell communication in uterine and umbilical vascular endothelium in pregnancy and the role of kinase activation in regulating those processes in preeclampsia.
1: Zhou C, Yan Q, Zou QY, Zhong XQ, Tyler CT, Magness RR, Bird IM, Zheng J. Sexual Dimorphisms of Preeclampsia-Dysregulated Transcriptomic Profiles and Cell Function in Fetal Endothelial Cells. Hypertension. 2019 Jul;74(1):154-163. doi: 10.1161/HYPERTENSIONAHA.118.12569. Epub 2019 Jun 3. PubMed PMID: 31154903; PubMed Central PMCID: PMC6561818.
2: Ampey AC, Boeldt DS, Clemente L, Grummer MA, Yi F, Magness RR, Bird IM. TNF-alpha inhibits pregnancy-adapted Ca(2+) signaling in uterine artery endothelial cells. Mol Cell Endocrinol. 2019 May 15;488:14-24. doi: 10.1016/j.mce.2019.02.008. Epub 2019 Feb 16. PubMed PMID: 30779937; PubMed Central PMCID: PMC6475486.
3: Zou QY, Zhao YJ, Zhou C, Liu AX, Zhong XQ, Yan Q, Li Y, Yi FX, Bird IM, Zheng J. G Protein α Subunit 14 Mediates Fibroblast Growth Factor 2-Induced Cellular Responses in Human Endothelial Cells. J Cell Physiol. 2019 Jul;234(7):10184-10195. doi: 10.1002/jcp.27688. Epub 2018 Nov 1. PubMed PMID: 30387149; PubMed Central PMCID: PMC6426666.
4: Ampey BC, Ampey AC, Lopez GE, Bird IM, Magness RR. Cyclic Nucleotides Differentially Regulate Cx43 Gap Junction Function in Uterine Artery Endothelial Cells From Pregnant Ewes. Hypertension. 2017 Aug;70(2):401-411. doi: 10.1161/HYPERTENSIONAHA.117.09113. Epub 2017 May 30. PubMed PMID: 28559397; PubMed Central PMCID: PMC5507815.
5: Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J Endocrinol. 2017 Jan;232(1):R27-R44. Epub 2016 Oct 11. Review. PubMed PMID: 27729465; PubMed Central PMCID: PMC5115955.
6: Anaya HA, Yi FX, Boeldt DS, Krupp J, Grummer MA, Shah DM, Bird IM. Changes in Ca2+ Signaling and Nitric Oxide Output by Human Umbilical Vein Endothelium in Diabetic and Gestational Diabetic Pregnancies. Biol Reprod. 2015 Sep;93(3):60. doi: 10.1095/biolreprod.115.128645. Epub 2015 Jul 22. PubMed PMID: 26203178; PubMed Central PMCID: PMC4710185.
7: Boeldt DS, Grummer MA, Yi F, Magness RR, Bird IM. Phosphorylation of Ser-279/282 and Tyr-265 positions on Cx43 as possible mediators of VEGF-165 inhibition of pregnancy-adapted Ca2+ burst function in ovine uterine artery endothelial cells. Mol Cell Endocrinol. 2015 Sep 5;412:73-84. doi: 10.1016/j.mce.2015.05.030. Epub 2015 May 29. PubMed PMID: 26033246; PubMed Central PMCID: PMC4516676.
8: Boeldt DS, Grummer MA, Magness RR, Bird IM. Altered VEGF-stimulated Ca2+ signaling in part underlies pregnancy-adapted eNOS activity in UAEC. J Endocrinol. 2014 Oct;223(1):1-11. doi: 10.1530/JOE-14-0252. Epub 2014 Jul 25. PubMed PMID: 25063757; PubMed Central PMCID: PMC4161637.
9: Boeldt DS, Hankes AC, Alvarez RE, Khurshid N, Balistreri M, Grummer MA, Yi F, Bird IM. Pregnancy programming and preeclampsia: identifying a human endothelial model to study pregnancy-adapted endothelial function and endothelial adaptive failure in preeclamptic subjects. Adv Exp Med Biol. 2014;814:27-47. doi: 10.1007/978-1-4939-1031-1_4. Review. PubMed PMID: 25015799.
10: Morschauser TJ, Ramadoss J, Koch JM, Yi FX, Lopez GE, Bird IM, Magness RR. Local effects of pregnancy on connexin proteins that mediate Ca2+-associated uterine endothelial NO synthesis. Hypertension. 2014 Mar;63(3):589-94. doi: 10.1161/HYPERTENSIONAHA.113.01171. Epub 2013 Dec 23. PubMed PMID: 24366080; PubMed Central PMCID: PMC3945210.
11: Bird IM, Boeldt DS, Krupp J, Grummer MA, Yi FX, Magness RR. Pregnancy, programming and preeclampsia: gap junctions at the nexus of pregnancy-induced adaptation of endothelial function and endothelial adaptive failure in PE. Curr Vasc Pharmacol. 2013 Sep;11(5):712-29. Review. PubMed PMID: 24063383.
Mechanisms of Endothelial and Embryonic Stem Cell Regulation in Pregnancy
Start Date: 12/1/2006 --- End Date: 11/30/2012
Sponsor: NIH P01 HD038843 (Bird Project 1 PI, Core C CoPI)
Studies under this proposal sought to further our understanding of the basic control of placental and uterine perfusion and mechanisms contributing to fetal pathophysiology in conditions such as pre-eclampsia and IUGR.
1: Bird IM. Endothelial nitric oxide synthase activation and nitric oxide function: new light through old windows. J Endocrinol. 2011 Sep;210(3):239-41. doi: 10.1530/JOE-11-0216. PubMed PMID: 21824899.
2: Boeldt DS, Yi FX, Bird IM. eNOS activation and NO function: pregnancy adaptive programming of capacitative entry responses alters nitric oxide (NO) output in vascular endothelium--new insights into eNOS regulation through adaptive cell signaling. J Endocrinol. 2011 Sep;210(3):243-58. doi: 10.1530/JOE-11-0053. Epub 2011 May 9. Review. PubMed PMID: 21555345; PubMed Central PMCID: PMC4059042.
3: Yi FX, Boeldt DS, Magness RR, Bird IM. [Ca2+]i signaling vs. eNOS expression as determinants of NO output in uterine artery endothelium: relative roles in pregnancy adaptation and reversal by VEGF165. Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1182-93. doi: 10.1152/ajpheart.01108.2010. Epub 2011 Jan 14. PubMed PMID: 21239633; PubMed Central PMCID: PMC3075018.
4: Yi FX, Boeldt DS, Gifford SM, Sullivan JA, Grummer MA, Magness RR, Bird IM. Pregnancy enhances sustained Ca2+ bursts and endothelial nitric oxide synthase activation in ovine uterine artery endothelial cells through increased connexin 43 function. Biol Reprod. 2010 Jan;82(1):66-75. doi: 10.1095/biolreprod.109.078253. Epub 2009 Sep 9. PubMed PMID: 19741206; PubMed Central PMCID: PMC2802114.
5: Grummer MA, Sullivan JA, Magness RR, Bird IM. Vascular endothelial growth factor acts through novel, pregnancy-enhanced receptor signalling pathways to stimulate endothelial nitric oxide synthase activity in uterine artery endothelial cells. Biochem J. 2009 Jan 15;417(2):501-11. doi: 10.1042/BJ20081013. PubMed PMID: 18816248; PubMed Central PMCID: PMC2680709.
6: Gifford SM, Yi FX, Bird IM. Pregnancy-enhanced store-operated Ca2+ channel function in uterine artery endothelial cells is associated with enhanced agonist-specific transient receptor potential channel 3-inositol 1,4,5-trisphosphate receptor 2 interaction. J Endocrinol. 2006 Aug;190(2):385-95. PubMed PMID: 16899571.
7: Gifford SM, Yi FX, Bird IM. Pregnancy-enhanced Ca2+ responses to ATP in uterine artery endothelial cells is due to greater capacitative Ca2+ entry rather than altered receptor coupling. J Endocrinol. 2006 Aug;190(2):373-84. PubMed PMID: 16899570.
8: Cale JM, Bird IM. Inhibition of MEK/ERK1/2 signalling alters endothelial nitric oxide synthase activity in an agonist-dependent manner. Biochem J. 2006 Sep 1;398(2):279-88. PubMed PMID: 16716148; PubMed Central PMCID: PMC1550315.
9: Sullivan JA, Grummer MA, Yi FX, Bird IM. Pregnancy-enhanced endothelial nitric oxide synthase (eNOS) activation in uterine artery endothelial cells shows altered sensitivity to Ca2+, U0126, and wortmannin but not LY294002—evidence that pregnancy adaptation of eNOS activation occurs at multiple levels of cell signaling. Endocrinology. 2006 May;147(5):2442-57. Epub 2006 Feb 2. PubMed PMID: 16455784.
10: Cale JM, Bird IM. Dissociation of endothelial nitric oxide synthase phosphorylation and activity in uterine artery endothelial cells. Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1433-45. Epub 2005 Nov 4. PubMed PMID: 16272197.
Placental Angiogenic Factors& Endothelial NO Production
Start Date: 4/1/2000 --- End Date: 3/31/2006
Sponsor: NIH P01 HD38843 (Bird Project 1 PI, Core 2 PI)
These studies provided a significant advance in both the understanding of normal control and coordination of Uterine artery and Placental artery endothelial function and the mechanism underlying pregnancy-induction of increased Uterine artery refractoriness to a variety of vasoconstrictors. As such they provided a new model of endothelial cell function on which future studies searching for the maternal and feto-placental vascular dysfunction leading to preeclampsia and IUGR were based.
Dr. Hoppe and Dr. Bird work together on the CHAPS trial.