Biochemical, genetic, and clinical evidence indicates that the Bone Morphogenetic Protein Receptors (BMPRs) play an essential role in the pathogenesis of pulmonary hypertension. BPMR2 mutations have found to be linked to familial cases of pulmonary hypertension, and this receptor has been shown to complex and stimulate intracellular signaling via its sister receptors, BMPR1A and B. The focus of this proposal is to understand the role of the BMPR1A and B as well as the downstream effectors of BMPR signaling, the dominant-negative Id transcription factors, in the development of pulmonary hypertension. Recently, we have linked the genetic mechanism of familial and sporadic pulmonary hypertension by showing that BMPR1A is downregulated at the level of transcription in the lung tissue from patients with multiple kinds of non-familial pulmonary hypertension by an Angiopoietin-1/TIE2 pathway. Building on this result, we have shown that Id1, a dominant negative represser of specific basic helix-loop-helix transcription factors is a downstream effector of BMPR signaling. We have demonstrated that levels of Id1 are decreased in the lungs of patients with several kinds pulmonary hypertension as well as rodents with monocrotaline and hypoxic pulmonary hypertension. Id proteins have been found to control expression of genes involved in cellular proliferation and cell cycle progression. Based on these results, we hypothesize the pathologic remodeling of small vessels in the lung in pulmonary hypertension is governed by and Ang-1/BMPR/ld signaling pathway. We propose to extend these findings in order to solidify and clarify the role of BMPR1A, BMPR1B, and Id 1-3 in pulmonary hypertension. To this end, we will: 1) investigate whether targeted inhibition of BMPR1A/B expression in either pulmonary endothelium and/or pulmonary smooth muscle in vivo, using conditional cell- specific knockout mice, will induce the pulmonary hypertensive phenotype, 2) characterize how defective BMPR signaling modulates the downstream inhibitory factors, ld1-3 and study the pattern of expression of these dominant negative transcription factors in human and rodent pulmonary hypertensive lung tissue, and 3) characterize the effect of Id protein expression on pulmonary vascular smooth muscle cell and endothelial proliferation. Information gained from these proposed experiments should elucidate a molecular mechanism for pulmonary hypertension and suggest possible treatment strategies for this disease. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Lathen, Christopher; Zhang, Yu; Chow, Jennifer et al. (2015) Response to Letter Regarding Article, ""The ERG-APLNR Axis Controls Pulmonary Venule Endothelial Proliferation in Pulmonary Veno-Occlusive Disease"". Circulation 132:e17
Lathen, Christopher; Zhang, Yu; Chow, Jennifer et al. (2014) ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. Circulation 130:1179-91
Thistlethwaite, Patricia A; Renner, John; Duhamel, David et al. (2011) Surgical management of endobronchial inflammatory myofibroblastic tumors. Ann Thorac Surg 91:367-72
Anile, Marco; De Giacomo, Tiziano; Venuta, Federico (2009) Endoscopic treatment of airway stenosis after lung transplantation. J Thorac Cardiovasc Surg 138:252; author reply 252-3
Li, Xiaodong; Zhang, Xiaoxue; Leathers, Robin et al. (2009) Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat Med 15:1289-97
Thistlethwaite, Patricia A; Yung, Gordon; Kemp, Aaron et al. (2008) Airway stenoses after lung transplantation: incidence, management, and outcome. J Thorac Cardiovasc Surg 136:1569-75
Kaneko, Kan; Li, Xiaodong; Zhang, Xiaoxue et al. (2008) Endothelial expression of bone morphogenetic protein receptor type 1a is required for atrioventricular valve formation. Ann Thorac Surg 85:2090-8
Thistlethwaite, Patricia A; Kemp, Aaron; Du, Lingling et al. (2006) Outcomes of pulmonary endarterectomy for treatment of extreme thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg 131:307-13
Thistlethwaite, Patricia A; Madani, Michael M; Kemp, Aaron D et al. (2006) Venovenous extracorporeal life support after pulmonary endarterectomy: indications, techniques, and outcomes. Ann Thorac Surg 82:2139-45
Thistlethwaite, Patricia A; Madani, Michael; Jamieson, Stuart W (2006) Outcomes of pulmonary endarterectomy surgery. Semin Thorac Cardiovasc Surg 18:257-64

Showing the most recent 10 out of 16 publications