The research laboratory of Simon Conway, PhD, is focused on examination and manipulation of the molecular regulatory mechanisms that govern cardiopulmonary development and disease. The lab specializes in using transgenic mouse modeling approaches to understand pathogenesis. With these models, the Conway Lab seeks to identify the mechanisms and cell lineages responsible for disease development and transgenically and/or pharmacologically correct the various structural and functional defects.
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Over the last 19 years, the Conway Lab has primarily focused on the pathogenesis of transcription factors Pax3/7 and the transforming growth factor-beta (TGFβ) superfamily mediated cardiac neural crest (NC)-associated congenital conotruncal heart defects.
Conotruncal heart defects (CHDs) result from a failure of the aorta and pulmonary trunks of the outflow tract (OFT) to become separate blood vessels. These defects are frequently associated with endocardial cushion/valve anomalies, and mutant mice exhibiting these CHDs often exhibit bradycardia and die in utero. Furthermore, lack of NC-mediated OFT septation often results in respiratory failure and abnormal lung maturation. Through the use of both physiological hyperoxia and transgenic approaches, the lab is testing whether initial suppression of the TGFβ signaling apparatus, as well as loss of key downstream TGFβ superfamily effectors, underlie lung malformations.
Recently, the lab has become interested in the cardiopulmonary roles of the TGFβ-responsive Periostin and TGFBI matricellular proteins. Significantly, the lab has shown that a partial Periostin element is uniquely capable of driving reporter expression in activated cardiac myofibroblasts, providing a unique in vivo tool for genetic manipulation of activated injury-site fibroblasts. Additionally, the lab generated Periostin and TGFBI knockout mice to test their functional requirement in heart and lung maturation, their responses to injury and their roles during multi-organ homeostasis and fibrosis.
Studies conducted in the Conway Lab contribute significantly to the current understanding of cardiopulmonary defect pathogenesis and seek to use basic research to uncover novel therapeutic approaches for the diagnosis and mitigation of life-threatening diseases routinely seen in the clinic.
R01 HL60714Molecular Mechanisms of Neural Crest-Related Congenital Heart Defects
Goals: To examine how Pax3 transcription factor regulates cardiac neural crest morphogenesis and determine the underlying mechanism of in utero heart failure in Pax3 nulls using systemic null, hypomorphic and lineage-restricted conditional mouse mutant models.
R01 HL135657Mechanisms of adult cardiac and pulmonary fibrosis in relation to TGFβ signaling and miR-145 function.
Goals: Test whether microRNA miR145 regulates adult heart and lung fibrosis via regulation of downstream Periostin matricellular protein.
VA BX002764Mechanisms associated with systemic effects of cancer.
Goals: Test hypothesis that cancer-derived cytokine TNFα contributes to impairment of cardiac and muscle functions in part by suppressing systemic levels of miR-486.
Kong P, Shinde AV, Su Y, Russo I, Chen B, Saxena A, Conway SJ, Graff JM, Frangogiannis NG. (2018). Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium. Circulation. 137:707-724. PMID:29229611
Alvarez M, Xu L, Himes E, Chitteti B, Childress P, Mohamad S, Olivos D, Cheng Y-H, Conway SJ, Srour EF, Kacena MA. (2018). Megakaryocyte and osteoblast interactions modulate bone mass and hematopoiesis. Stem Cells Dev. doi: 10.1089/scd.2017.0178. PMID:29631496
Duchamp de Lageneste O, Julien A, Abou-Khalil R, Frangi G, Carvalho C, Cagnard N, Cordier C, Conway SJ, Colnot C. (2018). Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin. Nat Commun. 9:773. doi: 10.1038/s41467-018-03124-z. PMID:29472541
Nakazeki F, Nishiga M, Horie T, Nishi H, Nakashima Y, Baba O, Kuwabara Y, Nishino T, Nakao T, Ide Y, Koyama S, Kimura M, TsujiS, Sowa N, Yoshida S, Conway SJ, Kimura T, and Ono K. (2018). Loss of periostin ameliorates adipose tissue inflammation and fibrosis in vivo. Sci Rep.
Schwanekamp JA, Lorts A, Sargent M, York AJ, Gokey J, Whitsett JA, Conway SJ and Molkentin JD. (2017). TGFBI functions similar to Periostin but is uniquely dispensable during cardiac injury. PLOS One, 12:e0181945. PMID:28750100
Poulsen ET, Runager K, Nielsen N, Thomsen K, Snider P, Simmons O, Vorum H, Conway SJ* and Enghild JL*. (2017). Proteomic profiling of Tgfbi-null mouse corneas reveals only minor changes in matrix composition supportive of TGFBI knockdown as therapy against TGFBI-linked corneal dystrophies. FEBS, 285:101-114 [* joint corresponding authors]. PMID:29117645
Nishiga M, Horie T, Kuwabara Y, Nagao K, Baba O, Nakao T, Nishino T, Izuhara M, Usami S, Hakuno D, Nakashima Y, Nakazeki N, Ide Y, Koyama S, Kimura M, Hanada R, Nakamura T, Hasegawa K, Conway SJ, Kita T, Kimura T, Ono K. (2017). MicroRNA-33 controls adaptive fibrotic response in the remodeling heart by preserving lipid raft cholesterol. Circ Res., 120:834-874. PMID:27920122
Rubart M, Tao W, Lu X, Conway SJ, Reuter S, Lin SF, Soonpaa M. (2017). Electrical coupling between ventricular myocytes and myofibroblasts in the infarcted mouse heart. Cardiovasc. Res., Sep 1. doi: 10.1093/cvr/cvx163. PMID:29016731
Ahlfeld SK, Wang J, Gao Y, Snider P, Conway SJ. (2016). Initial suppression of TGFβ signaling and loss of TGFBI causes early alveolar structural defects resulting in bronchopulmonary dysplasia. Am J Pathol. 186:777-93. PMID:26878215
Zhou HM and Conway SJ. (2016). Restricted Pax3 deletion in the neural tube results in congenital hydrocephalus. J. Dev. Biol. 4(1), 7; doi:10.3390/jdb4010007. PMCID:PMC4777317
Kaur H, Takefuji M, Ngai CY, Carvalho J, Bayer J, Wietelmann A, Poetsch A, Hoelper S, Conway SJ, Looso M, Möllmann H, Troidl C, Offermanns S, Wettschureck N. (2016). Targeted ablation of Periostin-expressing activated fibroblasts prevents adverse cardiac remodeling in mice. Circ Res., 118:1906-17. PMID:27140435
Gomez M, Wirrig E, Hassel K, Conway SJ, Yutzey KE. (2016). BMP signaling is required for aortic valve calcification. Arterioscler Thromb Vasc Biol., 36:1398-405. PMID:27199449
Walker JT, McLeod K, Kim S, Conway SJ, Hamilton DW. (2016). Periostin as a multifunctional modulator of the wound healing response. Cell Tissue Res., 365(3):453-65. PMID:27234502
Simmons O, Snider P, Wang J, Schwartz RJ, Chen YP and Conway SJ. (2015). Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality. Dev. Dyn. 244:457-67. PMID:25428115
Ahlfeld SK, Gao Y, Conway SJ, Tepper R. (2015). Relation of structural to functional impairment of alveolar-capillary membrane development. Am J Pathol. S0002-9440(15)00014-0. PMID:25661110
Sawaki D, Hou L, Tomida S, Zhan H, Aizawa K, Son BK, Otsu K, Conway SJ, Manabe I, Komuro I, Friedman S, Nagai R and Suzuki T. (2015). Modulation of cardiac fibrosis by Krüppel-like Factor 6 through transcriptional control of Thrombospondin-4 in cardiomyocytes. Cardiovasc Res., 107(4):420-30. PMID:25987545
McGrath KE, Frame JM, Fegan KH, Bowen JR, Conway SJ, Catherman SC, Kingsley PD, Koniski AD, Palis J. (2015). Distinct Sources of Hematopoietic Progenitors Emerge before HSCs and Provide Functional Blood Cells in the Mammalian Embryo. Cell Rep. 11(12):1892-904. PMID:26095363
Lajiness JD, Snider P, Wang P, Feng GS, Krenz M and Conway SJ. (2014). Shp2 deletion in post-migratory neural crest cells results in impaired cardiac sympathetic innervation. Proc Natl Acad Sci USA., 111:E1374-82. PMID:2470681
Snider P, Simmons O, Wang J, Hoang CQ and Conway SJ. (2014). Ectopic Noggin in a population of Nfatc1 lineage endocardial progenitors induces embryonic lethality. J. Cardiovasc. Dev. Dis., 1(3), 214-236. PMID:26090377
Rios HF, Bonewald L and Conway SJ. (2014). Lessons from the matricellular factor periostin. J Dent Res., 93(9):843-5. PMID:25012809
Simmons O, Bolanis EM, Wang J and Conway SJ. (2014). In situ hybridization (both radioactive and non-radioactive) and spatiotemporal gene expression analysis. Methods Mol Biol., 1194: 225-44. PMID:25064106
Conway SJ, Izuhara K, Kudo Y, Litvin J, Markwald R, Ouyang G, Arron JR, Holweg CT, Kudo A. (2014). The role of periostin in tissue remodeling across health and disease. Cell Mol Life Sci., 85(4):845-54. PMID:24146092
Ahlfeld SK and Conway SJ. (2014). Assessment of inhibited alveolar-capillary membrane structural development and function in bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol., 100(3): 168-180. PMID: 24604816
Abman SH and Conway SJ. (2014). Developmental determinants and changing patterns of respiratory outcomes after preterm birth. Birth Defects Res A Clin Mol Ter., 100(3): 127-134. [Cover article] PMID:2465939
Lajiness J and Conway SJ. (2014). Origin, development and differentiation of cardiac fibroblasts. J Mol Cell Cardiol., 70:2-8. PMID:24231799