Identification of the Functional Role of Dysferlin

Objective: 
Explore the possible functional roles of dysferlin

Although it proposed that dysferlin plays a key role in rapid calcium-mediated membrane resealing, very little is known regarding how it performs this role. The seven putative C2 domains within dysferlin suggest a high degree of modulation by intracellular calcium, likely mediating interactions central to its role in membrane repair. We are studying the cellular biology of dysferlin in cultured muscle cells, and have developed two membrane repair assays to study the functional role of dysferlin in membrane repair.

Research

Molecular-Functional Comparison of the Dysferlin Membrane Repair Complex with the Otoferlin Synaptic Complex

Objective: 
To compare the molecular function of dysferlin and otoferlin.

Genetically-defective dysferlin causes LGMD2B muscular dystrophy and mutated otoferlin causes DFNB9 deafness. Both proteins normally function by forming complexes with other proteins that either repair muscle (dysferlin) or promote hearing through sound-signal transmission (otoferlin). We are investigating the molecular role of dysferlin in muscle, guided by known ferlin interactions in inner ear hair cells, in an examination of the generalized molecular properties of dysferlin across tissues.

Research

Enhanced AAV Vectors for Dysferlin Gene Delivery and Evaluation in a Dysferlin Deficient Mouse Model of Muscle Regeneration

Objective: 
Application of Emerging AAV Vector Advancements for the Treatment of Dysferlinopathy

AAV gene therapy approaches for the treatment of dysferlinopathy have demonstrated efficacy in animal models using dual vectors or fragmented preparations capable of mediating oversized gene transduction.  These approaches, while effective and interesting from a basic genetic standpoint, suffer from decreased transduction efficiencies.  In particular, our work has demonstrated a concentration dependent effect:  there is a larger transduction deficit for a multiple vector approach when the vector genomes are diluted (i.e.

Research

Developing a Multi-Pronged Strategy for the Clinical Management of Dysferlinopathies

Objective: 
The broad objective of our research is to develop a better understanding of how skeletal muscles adapt to mechanical loading from exercise.

Our data from earlier studies funded by the Jain Foundation suggest that intense loading of dysferlin-deficient murine skeletal muscle during exercise, does not cause acute muscle damage, but rather, causes extensive damage and inflammation that accrues over several days after loading.  Our current Jain Foundation funded project is aimed at developing exercise programs that have the potential to reduce post-exercise muscle damage and inflammation in dysferlin-deficient skeletal muscle.  We anticipate that our studies will provide useful information regarding exercise to patients with dysfer

Past

Biochemical and Therapeutic Characterization of Dysferlin

Objective: 
Characterize and evaluate the therapeutic potential of recombinant membrane repair proteins.

We express and purify recombinant dysferlin proteins and are using an assortment of biochemical, biophysical, and microscopy assays to better understand how dysferlin regulates membrane structure and membrane fusion.  The aims of this project are to 1) investigate the therapeutic potential of candidate small molecules by assessing their ability to restore function to recombinant dysferlin proteins harboring disease-causing mutations, and 2) investigate how alternative splicing of the dysferlin transcript affects the structure and lipid-binding activities of the resultant protein.

Research

Identification of Genetic Suppressors of C. Elegans Fer-1

Objective: 
Identify and characterize genetic and chemical suppressors of C. elegans fer-1 as a way to identify potential new therapeutic targets

C. elegans fer-1 is the ancestral homolog of human Dysferlin. Mutations in fer-1 are known to cause infertility in C. elegans. Since genetic modifiers of LGMD2B/MM are known to exist, it is possible that homologous modifiers may also exist in other organisms such as C. elegans. Based on this rationale, we performed a large-scale mutagenic screen and isolated a number of genetic suppressor mutants that restore fertility to C.

Past

2B Empowered Conference

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Disease-modifying factors in inherited muscle diseases, a twin study

Objective: 
The objective of this project is to understand whether progression of LGMDs is due to genetics or environment.

Phenotypic variation has been reported in patients with the same inherited muscle disease, even  with identical gene mutations, inter- and intrafamilially. 

The goal of this project is

(i) to investigate if there is a variability in onset, progression and symptoms in monozygotic and dizygotic twins  with inherited muscle diseases, with primary focus on muscular dystrophies like dysferlinopathies.

Past

Hasan Balcin, M.D

Karolinska University Hospital, Huddinge

Dr. Balcin is a postdoctoral research fellow at the Karolinska Institute in the Department of Neurophysiology and Neurology in Stockholm, Sweden.

Past Projects

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