Projects

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Project 1

The Kunkel Laboratory

Gene expression and biochemical studies of filamin/sarcoglycan-related dystrophies.

Directed by the Program Director, Dr. Lou Kunkel, this project will continue his laboratory's interest in understanding the underlying basis of the muscular dystrophies and using that information to develop targeted treatments. Project 1 will focus on a subset of the Kunkel laboratory's effort, with emphasis on the role of the sarcoglycans and newly identified filamin-2 in the pathogenesis of the limb girdle muscular dystrophies (LGMD). We will explore this function via conventional biochemical and genetic analysis, and by the new expression array (Core C). We will have the unique opportunity to study the mRNA expression profiles of the different muscle biopsies we have collected over the years and plan to collect as part of this program in collaboration with Core B. These expression patterns will be confirmed by our ongoing biochemical work on muscle proteins in the muscular dystrophies. We also are very excited about the possibilities of our recently described muscle stem cells and their potential role in developing a therapy for muscle disorders. These will be studied in collaboration with project 4 to determine their existence in dystrophies and whether normal cells will be equally effective as they were in dystrophin-deficient mice.

Aims:

  • To continue the analysis of Filamin 2 as a new component of the dystrophin associated protein complex and its role in LGMD.
  • To identify additional novel FLNC/sarcoglycan-associated interacting proteins by yeast two-hybrid and biochemical cross-linking of proteins made in muscle.
  • To use chip-based mRNA expression arrays to analyze/compare dystrophin, sarcoglycan, calpain-3 and filamin-deficient muscle to normal muscle in order to identify changes that are common among the dystrophies or specific to a particular form of dystrophy.
  • To validate results of expression arrays and characterize genes that are unique to each of the dystrophies as potential modifiers of the phenotype and begin to test new hypotheses about the molecular pathogenesis of muscle degeneration.
  • To analyze SP stem cell populations within sarcoglycan-deficient mouse models of human dystrophy, studying the influence these mutations have on the stem cells and whether normal stem cells can be corrective in these respective dystrophies.

If you are interested in participating in this project or learning more about our research, please visit the Kunkel Laboratory website.

Project 2

The Brown Laboratory (Day Neuromuscular Research Laboratory)

Gene expression and biochemical studies of dysferlin-related dystrophies.

Dr. Brown is trying to characterize the biological properties of dysferlin and its role in the pathogenesis of limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), and to initiate studies of cell therapy in these two diseases. These biological studies will entail an investigation of dysferlin-interacting proteins, using both conventional and newer (microarray) methods. The cell therapy studies will characterize muscle stem cells in dysferlin-deficient mice and assess the feasibility of using normal muscle stem cells to replace dysferlin in these animals.

Aims:

  • To characterize dysferlin gene mutations and abnormalities of dysferlin protein expression in patients with MM and LGMD 2B and use this information to extend our studies of dysferlin as a novel muscle membrane protein.
  • To identify proteins that interact with normal and mutant dysferlin via conventional analysis.
  • To use chip-based mRNA expression to analyze/compare dysferlin-deficient human muscle to identify changes of muscle gene expression that are either common to all dystrophies or specific to the dysferlinopathies.
  • To validate results of expression arrays and characterize genes that are unique to each of the dystrophies as potential modifiers of the phenotype and begin to test new hypotheses about the molecular pathogenesis of muscle degeneration in the dysferlinopathies.
  • To analyze SP cell populations in MM and LGMD 2B in a mouse model of dysferlin deficiency.

If you are interested in participating in this project or learning more about our research, please visit the Brown Laboratory (Day Neuromuscular Research Laboratory) website.


Project 3

The Beggs Laboratory

Gene Expression and Biochemical Analysis of Muscle Development in Myotubular Myopathy.

The goal of this Project is to understand the molecular basis for X-linked myotubular myopathy (XLMTM) by determining the effects of myotubularin mutations on gene expression. Pathologically, XLMTM is characterized by incomplete muscle maturation caused by defects in myotubularin, a dual specificity protein phosphatase. This study entails the developmental characterization of global gene expression of known genes and novel expressed sequence tags (ESTs) in XLMTM and related disorders from the SP stem cell stage through to mature muscle. Understanding perturbations in gene expression will shed light on the function of myotubularin and its role in normal muscle development and may allow identification of therapeutic targets to stimulate normal muscle development in patients with XLMTM and related disorders of muscle development.

Aims:

  • To ascertain and characterize fresh muscle, muscle cell cultures and frozen muscle biopsies from patients with XLMTM and CTNM.
  • To isolate and characterize muscle stem cells (SP cells) from myotubularin-deficient patients. To use chip-based mRNA expression arrays to analyze perturbations of gene expression associated with abnormalities of myotubularin in cultured muscle cells.
  • To use chip-based mRNA expression arrays to analyze/compare XLMTM and CTNM human muscle to identify disease-specific and nonspecific changes in muscle gene expression.
  • To validate results of expression arrays and characterize genes whose expression is specifically perturbed by myotubularin dysfunction.

If you are interested in participating in this project or learning more about our research, please visit the Beggs Laboratory website.

Project 4 

The Gussoni Laboratory

Gene expression in, and therapeutic application of, muscle stem cells.

The long-term goals of this project are to isolate and characterize stem cells from human skeletal muscle, and test their ability to correct muscular deficiencies in-vivo. These studies will require the use of the fluorescence-activated cell sorter and microarray techniques to purify human muscle cells and identify the genes they specifically express. Human muscle stem cells will be introduced into the circulation of different animal models of muscle disorders and their ability to target and repair damaged muscle will be assessed.

Aims:

  • To optimize the isolation of muscle stem cells (SP cells) in humans.
  • To use chip-based mRNA expression arrays to identify genes expressed by human muscle SP cells.
  • To analyze candidate genes from gene chip technology using other conventional techniques.
  • To optimize conditions to propagate and culture human SP cells in vitro.
  • To evaluate the differentiation potential of human muscle SP cells in vivo.

If you are interested in participating in this project or learning more about our research, please visit the Gussoni Laboratory website.

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