The long-term goal of this project is to understand the role of laminins (LNs) in lung organogenesis. LNs are basement membrane glycoproteins essential for normal pulmonary development. During the current funding period we demonstrated the importance of laminin-1 (LN-1) and laminin-2 (LN-2) in promoting bronchial myogenesis. Now our objective is to understand the molecular pathway involved in this process Preliminary studies suggest that LN-1 and -2 stimulate myogenesis by a mechanism involving P311, j protein of uncertain function recently identified in neurons and muscle. Pilot studies focused in the developing mouse lung suggested that P311 is induced by LN-2 and to a lesser extent by LN-1. In addition, our studies suggested that the synthesis of the two LNs is mechano-sensitive. Based on these and other preliminary data presented here we hypothesize that LN regulates myogenesis by a signaling pathway that involves P311, depends on mechanical stimuli and engages GTPases as downstream effectors We will use a combination of embryonic mesenchymal cells and lung organ cultures from normal and dy/dy mice (no LN-2), plus a variety of functional probes to address this hypothesis.
In aim# l we will determine the role of P311 in lung development.
In aim #2 we will elucidate the involvement of LNs 2 and 1 and P311 in stretch-mediated bronchial myogenesis.
In aim #3 we will identify the downstream molecular pathway activated in LN/P311 stimulation of bronchial myogenesis. Part A of this aim will focus on the role of Cdc42 and RhoA. Part B will study P311 interaction with other proteins, including Vav2, a proto-oncogene that activates Cdc42 and RhoA. We expect this project to define a novel molecular pathway controlling bronchia myogenesis. This pathway may be common to various myogenic stimuli and is likely to be abnormal in lung disease, as our ongoing studies seem to indicate. We anticipate, therefore, that this project will advance our understanding of lungdevelopment as well as diseases caused by, or resulting from abnormal smooth muscle quantity, distribution and function.
| Badri, Kameswara Rao; Gao, Ling; Hyjek, Elizabeth et al. (2013) Exonic mutations of TSC2/TSC1 are common but not seen in all sporadic pulmonary lymphangioleiomyomatosis. Am J Respir Crit Care Med 187:663-5 |
| Badri, Kameswara Rao; Yue, Ming; Carretero, Oscar A et al. (2013) Blood pressure homeostasis is maintained by a P311-TGF-? axis. J Clin Invest 123:4502-12 |
