My main area of interest centres on the dysregulation of vascular stability in post-natal diseases. The main disease I study is pulmonary arterial hypertension, the major genetic cause being mutations in the bone morphogenetic type-II receptor (BMPR-II) gene, BMPR2. In endothelial cells, BMPR-II forms a signalling complex with the type I receptor, ALK1, this ALK1/BMPR-II complex mediating cellular responses to the circulating ligands BMP9 and BMP10. Intriguingly, ALK1 mutations underlie approximately 40% of hereditary haemorrhagic telangiectasia (HHT), although in rare cases, ALK1 mutations can cause PAH and HHT. Paradoxically, PAH is associated with increased vessel muscularisation whereas the vascular lesions in HHT are characterised by a deficiency of smooth muscle cell coverage.
Although the genetic lesions underlying PAH and HHT are known, both diseases are promoted by additional disease initiating and/or driving factors that may be genetic or somatic. Only 20% of BMPR2 mutation carriers develop PAH. In HHT families, related family member with the same mutation present vascular lesions in different organs.
My main research questions are:
1) What are the signalling pathways mediating BMPR2 and ALK1 signalling, particularly in response to BMP9 and BMP10. How do these pathways regulate to vascular cell responses?
2) How are BMP9 and BMP10 regulated in vivo and how are the levels of these ligands altered in disease?
3) How do potential disease-promoting pathways, such as the TNF-α and VEGF pathways, impact on BMP-dependent vascular cell functions?
4) Can we identify altered signalling of BMP or disease modifier pathways representing therapeutic targets in PAH?
vascular smooth muscle cells (VSMC) ; endothelial function ; bone morphogenetic protein
Collaborators outside this directory
- Dr Beth Roman - http://www.publichealth.pitt.edu/home/directory/beth-l-roman
- Dr Paul Yu - http://researchfaculty.brighamandwomens.org/BRIProfile.aspx?id=6116
- Dr Gareth Inman - http://medicine.dundee.ac.uk/staff-member/dr-gareth-j-inman
Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW.TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. (2017) Nat Commun. 8:14079.
Soon E, Crosby A, Southwood M, Yang P, Tajsic T, Toshner M, Appleby S, Shanahan CM, Bloch KD, Pepke-Zaba J, Upton P, Morrell NW. BMPR-II Deficiency Promotes Pulmonary Hypertension via Increased Inflammatory Cytokine Production. (2015) Am.J.Respir.Crit.Care Med. 859-72.
Long L, Ormiston ML, Yang X, Southwood M, Gräf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore SD, Drake KM, Aldred MA, Yu P, Upton PD*, Morrell NW* Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension (2015) Nat.Med.21(7):777-785.
Wooderchak-Donahue, WL, McDonald J, O'Fallon B, Upton PD., Li W, Roman BL, Young S, Plant P, Fulop GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR and Bayrak-Toydemir P. 2013. BMP9 Mutations Cause a Vascular-Anomaly Syndrome with Phenotypic Overlap with Hereditary Hemorrhagic Telangiectasia. (2013) Am.J.Hum.Genet. 93(3) 530-537
Upton PD, Davies RJ, Tajsic T, and Morrell NW. 2013. TGFbeta1 Represses BMP-Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells Via Smad3. (2013) Am.J.Respir.Cell Mol.Biol. 49(6) 1135-45
Laux DW, Young S, Donovan JP, Mansfield CJ, Upton PD and Roman BL. Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence. (2013) Development 140:3403-3412.