Very little is known about the development of the human intestinal muscle layers and associated extracellular matrices. The overall objective of this proposal is to analyze the ontogeny of intestinal smooth muscle cell function. There is evidence that smooth muscle cell number, the contractile state of the smooth muscle cell and the quantity and type of collagen produced by smooth muscle cells directly determines the integrity and compliance of the bowel wall. A recently established in vitro model has demonstrated that collagen production is a major function of adult intestinal smooth muscle cells. Collagen is essential for cell attachment, migration, proliferation and differentiation as well as providing a structural support for organs. These properties of collagen are crucial in organogenesis. Consequently, the development of intestinal structure and motility in utero and in infancy appears to depend not only on smooth muscle cell differentiation into proliferative and contractile states, but also depends on smooth muscle cell production of extracellular matrix components such as collagen. The factors which regulate smooth muscle cell differentiation and function in intestinal development remain unknown. Based upon observations in other developmental systems, it is most likely that hormones and growth factors play a central role. Therefore, this project will test the hypothesis that intestinal smooth muscle cell differentiation resulting in proliferative, matrix producing and contractile function is regulated during development by the age of the organism, the hormonal environment and polypeptide growth factors. Using the recently established in vitro model, the influence of hormones and growth factors on the following intestinal smooth muscle cell functions will be examined: 1) net collagen production, 2) expression of specific collagen types, 3) mechanism of collagen production, 4) cell proliferation and 5) contractile response. These studies will contrast various stages of fetal, neonatal, and adult intestinal smooth muscle cells. These findings will contribute to an understanding of the regulation of developing human intestinal smooth muscle cell function and how loss of this regulation clinically may result in intestinal strictures, atresias, duplications, hypoplasias, malrotation, gastroschisis, Hirschsprung's disease and motility disorders.
| Perr, H; Oh, P; Johnson, D (1996) Developmental regulation of transforming growth factor beta-mediated collagen synthesis in human intestinal muscle cells. Gastroenterology 110:92-101 |
| Perr, H A; Grider, J R; Mills, A S et al. (1992) Collagen production by human smooth muscle cells isolated during intestinal organogenesis. Anat Embryol (Berl) 185:517-27 |
