This mentored research plan is designed to facilitate the candidate's transition to the role of independent investigator and physician-scientist in the Division of Cardiovascular Medicine at Stanford University, broadening his knowledge base and research experience while unifying his interests in gene expression, vascular biology, and macromolecular interactions. The resources, opportunities and environment provided by the Division are ideal for the accomplishment of this plan. Dr. Quertermous, the project sponsor, is an established leader in vascular biology and a proven mentor. Each of the project's consultants (Phil Tsao, Gerald Crabtree, Gary Owens) add considerable depth of knowledge and expertise. The proposed project will examine the role of chromatin remodeling in smooth muscle cell phenotypic modulation. Smooth muscle cells (SMCs) play crucial roles in vascular development, homeostasis, and disease. Injury causes SMCs to modulate from a quiescent, differentiated state to a synthetic, proliferative phenotype. Details of SMC phenotypic switching in development and disease have remained elusive. Chromatin remodeling causes selective gene silencing and activation. In preliminary studies, we performed transcriptional profiling using an in vitro model of SMC differentiation, and identified several chromatin remodeling genes that were differentially regulated. We hypothesize that chromatin remodeling plays a key role in the expression of SMC specific genes, and in SMC phenotypic modulation. Our proposal describes a series of in vivo and in vitro experiments to investigate this hypothesis.
In Aim 1 we will use microarrays in a variety of models to identify candidate chromatin remodeling SMC proteins during phenotypic modulation.
In Aim 2. we will perturb these candidate genes in vitro with various techniques to assess their function in SMC differentiation.
In Aim 3. perturbations found to alter SMC differentiation during Aim 2 will be examined with chromatin immunoprecipitation combined with high-throughput techniques, identifying patterns of histone modifications in differentiating SMC that will be correlated with transcriptional patterns for candidate genes. This work will result in the characterization of SMC chromatin remodeling genes that affect both SMC marker expression and phenotypic switching. The project will also advance the candidate's experience in vascular biology, establish his research niche, and foster his career as an academic physician.
|Maegdefessel, Lars; Spin, Joshua M; Raaz, Uwe et al. (2014) miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nat Commun 5:5214|
|Maegdefessel, Lars; Spin, Joshua M; Adam, Matti et al. (2013) Micromanaging abdominal aortic aneurysms. Int J Mol Sci 14:14374-94|
|Maegdefessel, Lars; Azuma, Junya; Toh, Ryuji et al. (2012) Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J Clin Invest 122:497-506|
|Spin, Joshua M; Maegdefessel, Lars; Tsao, Philip S (2012) Vascular smooth muscle cell phenotypic plasticity: focus on chromatin remodelling. Cardiovasc Res 95:147-55|
|Leeper, Nicholas J; Raiesdana, Azad; Kojima, Yoko et al. (2011) MicroRNA-26a is a novel regulator of vascular smooth muscle cell function. J Cell Physiol 226:1035-43|
|Spin, Joshua M; Hsu, Mark; Azuma, Junya et al. (2011) Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm. Physiol Genomics 43:993-1003|
|Spin, Joshua M; Quertermous, Thomas; Tsao, Philip S (2010) Chromatin remodeling pathways in smooth muscle cell differentiation, and evidence for an integral role for p300. PLoS One 5:e14301|