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Research project

Understanding intestinal smooth muscle contraction

Status: ongoing

Smooth muscle contraction is important for the functioning of the gastrointestinal tract, but is impaired in several congenital intestinal disorders.

What we do

About our project

Background information

Normal motility of the gastrointestinal tract is reliant on complex patterns of smooth muscle contraction and the coordinated action of the enteric nervous system, smooth muscle cells and interstitial cells of Cajal. Developmental defects affecting the formation or proper functioning of one of these components, result in variable degrees of abnormal motility, and are the basis of intestinal neuromuscular disorders. In this project, we focus on the study of the smooth muscle to understand the mechanisms underlying intestinal myopathies, such as megacystis microcolon intestinal hypoperistalsis and congenital short bowel syndrome.

Overall aim?

This project has three main objectives:

  1. To determine how the human intestinal smooth muscle develops during embryogenesis. 
  2. To identify key components required for smooth muscle contraction and understand how this process occurs. 
  3. To apply the knowledge gathered to develop a new therapeutic approach for treating intestinal disorders arising from abnormal smooth muscle contraction.

Research method

We will use several techniques, such as expression profiling, protein analyses and functional assays. We will also develop a 3D in vitro model, gut-on-a-chip, that will mimic the organotypic features of the human intestine. This model will be composed of epithelial cells, smooth muscle cells and enteric ganglia, thus allowing us to study the interaction between different cell types, and test potential new therapies for intestinal disorders based on genetic correction. 

Desirable outcome

The results obtained will bring new insights into the development and functioning of the smooth muscle, and its contribution to the pathogenesis associated with intestinal myopathies. Moreover, we will develop a system that can be used to check the efficiency and applicability of genetic correction for the treatment of intestinal motility disorders in general. This may ultimately lead to improved management and quality of life of patients affected by such disorders.

Our research focus

To better understand the function of the intestinal smooth muscle, we study two congenital intestinal myopathies: Megacystis microcolon intestinal hypoperistalsis (MMIHS) and congenital short bowel syndrome (CSBS).

  • MMIHS is the most severe cause of intestinal and bladder obstruction in neonates, and is characterized by an enlarged bladder (megacystis) and the presence of a microcolon.  It is a genetic disorder and to date, five genes have been identified to cause MMIHS. Mutations in ACTG2 cause an autosomal dominant form of the disease, while mutations in MYH11, MYLK, LMOD1, and  MYL9 cause an autosomal recessive form of MMIHS.
  • CSBS is a congenital anomaly in which the child is born with a dramatically short small intestine. The intestinal absorptive surface is therefore reduced, as a consequence of which the child suffers from malabsorption. CSBS is a genetic disorder, and two genes have been associated to its development. Mutations in CLMP cause an autosomal recessive form of CSBS, while mutations in FLNA cause the X-linked form of the disease.

Treatment possibilities for both disorders are limited and most patients do not survive their first years of life. New therapeutic options that can improve the survival and quality of life of these patients should therefore be developed.


Collaborations within Erasmus MC

  • Department of Pediatric Surgery.
  • Department of Cell Biology.

Collaborations outside of Erasmus MC

  • Department of Molecular Cell Biology and Department of Human Genetics, Leiden University Medical Centre, Leiden.
  • The Leiden Academic Centre for Drug Research, Leiden.
  • Institute of Child Health, UCL Great Ormond Street.


Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.
Halim D, Brosens E, Muller F, Wangler M.F, Beaudet A.L, Lupski J.R, Akdemir Z.H.C, Doukas M, Stoop H.J, de Graaf B.M, Brouwer R.W.W, van Ijcken W.F.J, Oury J.F, Rosenblatt J, Burns A.J, Tibboel D, Hofstra R.M.W, Alves M.M. (2017) Am J Hum 101:123-129.

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice. Halim D, Wilson MP, Oliver D, Brosens E, Verheij JB, Han Y, Nanda V, Lyu Q, Doukas M, Stoop H, Brouwer RW, van IJcken WF, Slivano OJ, Burns AJ, Christie CK, de Mesy Bentley KL, Brooks AS, Tibboel D, Xu S, Jin ZG, Djuwantono T, Yan W, Alves MM, Hofstra RM1, Miano JM. (2017) Proc Natl Acad Sci U S A 114:E2739-E2747.

ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome. Halim D, Hofstra R.M, Signorile L, Verdijk R.M, van der Werf C.S, Sribudiani Y, Brouwer R.W, van IJcken W.F, Dahl N, Verheij J.B, Baumann C, Kerner J, van Bever Y, Galjart N, Wijnen R.M, Tibboel D, Burns A.J, Muller F, Brooks A.S, Alves M.M. (2016) Hum Mol Genet 25:571-583.

Genetics of enteric neuropathies.
Brosens E, Burns AJ, Brooks AS, Matera I, Borrego S, Ceccherini I, Tam PK, García-Barceló MM, Thapar N, Benninga MA, Hofstra RM, Alves MM. (2016). Dev Biol. 2016 Sep 15;417(2):198-208.

Our team

  • Maria Alves (Senior Scientist)
  • Yuying Zhao (PhD student)

Any questions?

Please contact our office if you have any questions or comments.

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