Mechanical forces play an important role both during bladder development and in several bladder-related pathophysiological processes. In particular, the normal cycling or volume work that occurs during bladder development is necessary to drive processes required for cell growth and differentiation. However, abnormal/excessive strain is suggested as the prime initiator of pathological remodeling that occurs as a result of anatomic or functional bladder outlet obstruction subsequent to neurogenic, prostatic, congenital and/or urethtral stricture diseases. We have recently accumulated several lines of evidence indicating that the immediate early growth factor referred to as Cyr61 (cysteine-rich protein 61) or CCN1 plays an important role in the response of bladder smooth muscle cells (SMCs) to mechanical stimulation. The expression of the Cyr61 gene is mediated via mechano-transduction pathways that are the prime means by which hypertrophic signals are transduced in the cells. Cyr61 protein activity seems to affect the expression of several muscle and non-muscle-specific genes. The current proposal consists of a strategy to tease out the proper effects of mechanical forces on gene expression in cultured bladder SMCs and determine the in vivo relevance of those molecular changes during bladder development. These goals will be achieved by addressing the following Specific Aims. In the first Aim, we will use microarray technology to examine the overlap, at the level of mRNA transcription, between mechanical stimulation and Cyr61 overexpression in cultured bladder SMCs. We will, first, identify common and/or unique clusters of genes associated with the application of acute (0.5 and 6 hours) and chronic (24 hours) mechanical stimulation using a mechanical stretch device. Second, we will identify the group of genes associated with the over-expression of Cyr61 using adenoviral gene transfer and microarray screening. Therefore, mechano-sensive genes whose expression is Cyr61- dependent will be identified. This global gene expression profiling will allow us to determine whether coregulated genes are related functionally and identify common and/or unique gene regulatory networks. In the second Aim, we will define the temporal and spatial expression of Cyr61 and Cyr61-targeted genes in the developing bladder and determine whether these mechano-sensitive genes play a role during tissue specification with particular emphasis on detrusor smooth muscle differentiation. These studies will allow us to define the key molecular intermediates that convert the mechanical signals into biological responses and generate new biologically meaningful hypotheses as to the role of potential molecular targets in bladder development and obstructive diseases. ? ? ?
| Hanna, Mary; Liu, Haibo; Amir, Jawaria et al. (2009) Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase. J Biol Chem 284:23125-36 |
| Yang, Ru; Amir, Jawaria; Liu, Haibo et al. (2008) Mechanical strain activates a program of genes functionally involved in paracrine signaling of angiogenesis. Physiol Genomics 36:1-14 |
| Chaqour, Brahim; Goppelt-Struebe, Margarete (2006) Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. FEBS J 273:3639-49 |
| Zhou, Dongming; Herrick, David J; Rosenbloom, Joel et al. (2005) Cyr61 mediates the expression of VEGF, alphav-integrin, and alpha-actin genes through cytoskeletally based mechanotransduction mechanisms in bladder smooth muscle cells. J Appl Physiol 98:2344-54 |
