Molecular Mechanisms of Pulmonary Hypertension

University Of California, San Diego, La Jolla CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] [unreadable]