Functional Analysis of the digestive tract in mdx mice

Progetto: Research project


Objective - This project is direct forward the analysis of the mechanisms underlying the altered intestinal motility observed in mdx mice, animal models for studying dystrophic process, using functional, pharmacological and electrophysiological approaches. Background/rationale - Duchenne muscular dystrophy (DMD) is a genetic disease caused by the absence of dystrophin, cytoskeletal protein localised at the plasma membrane in muscles and in neurons. One of the hypothesises put forward to understand how the lack of dystrophin causes muscle dysfunctions speculates that a nitric oxide synthase (nNOS)-related defect may contribute to the pathophysiology of DMD. Nitric oxide (NO) is one of the main control systems in the gastrointestinal tract, making this preparation suitable for correlate abnormalities in NO system to the pathological process. We have previously shown alterations in the mdx mice gastrointestinal motor and electrical pattern attributed to an impairment of nitric oxide function. The reduction of the NO inhibitory influence would cause dysregulation of Ca2+ homeostasis in the smooth muscle cells. Description of the project - We plane to investigate, studying the mechanical and electrical activity of different portions of gastrointestinal tract in mdx mice i) how an impairment of NO can lead to a dysregulation of Ca2+ homeostasis; ii) if, in addition to a primary defect in nNOS, destruction of the transduction machinery in the muscle cells may contribute to disease processes, iii) if the reduction of the NO inhibitory influence can be coupled with an over-expression of other possible neurotransmitters, or with defects in other control nervous pathways. Anticipated outcome – Results from these studies, could be helpful to gain new insight the relationship among dystrophin, Ca2+ homeostasis and NO and, therefore, to clarify some aspects of the dystrophic process.

Layman's description

The research which we plan to perform is an extension of the studies already carried out in our laboratories and it is concerning the analysis the mechanisms underlying the alterations of the intestinal motor dysfunctions observed in the gastrointestinal tract of mdx mice. In fact, our previous studies have demonstrated that the mdx gastrointestinal smooth muscle undergoes to functional alterations which make this preparation available to understand the pathogenic mechanisms responsible for the dystrophic disease. Functional, pharmacological and electrophysiological investigations will be performed, in parallel, in order to better clarify the relationship among absence of dystrophin in the smooth muscle cells, homestasis of Ca2+ and impairment of nitric oxide function. Moreover, despite the defects in mechanical activity some form of propulsive behaviour persists in mdx mice, studies will be also addressed to explore possible neural or myogenic mechanisms able to compensate the impairment of the NO function in mdx gastrointestinal tract.
Data di inizio/fine effettiva1/1/03 → …