Liza Pon, professor in the department of pathology and cell biology at Columbia University in New York was awarded an MDA research grant totaling $300,000 over three years to study the underlying mechanisms at work in CHKB congenital muscular dystrophy (CMD). Pon also will test whether therapies that promote function of a protein known as the ryanodine receptor (RyR), which plays a critical role in contraction of skeletal and heart muscle, can promote muscle function or prevent muscle degeneration in a mouse model for CHKB CMD and in muscle cells taken from CHKB CMD patients.
Please describe your current research.
Congenital muscular dystrophy, one of the most frequent dystrophies of childhood, is characterized by neonatal poor muscle tone, muscle weakness, stiff or frozen joints and delayed motor milestones. The focal point of my studies is CHKB CMD, a newly identified CMD in which patients exhibit generalized muscle wasting and weakness from early infancy with ambulatory delays. Although there is no obvious defect in brain development, all CHKB CMD patients experience severe mental retardation, and most never acquire meaningful language. CHKB CMD patients can die as early as 2 years of age from loss of heart function. Currently, there is no cure for CHKB CMD. We will study the mechanism underlying CHKB CMD and possible therapeutic interventions.
Early studies revealed that the CHKB CMD is produced by a mutation in the choline kinase beta (CHKB), a protein that is responsible for synthesis of a lipid (phosphatidylcholine) that is found in cell membranes. We found that the lipid imbalance produced by this mutation has a negative impact on proteins within membranes and on a specific membrane protein known as the Ryanodine Receptor (RyR).
The RyR is critical for contraction of skeletal and heart muscle, and mutation of the RyR is the basis for a number of muscular dystrophies and heart diseases. We will test whether defects in the RyR are the basis for CHKB CMD. We will also test whether therapies that promote RyR function and/or restore lipid balance can promote muscle function or prevent muscle degeneration in a mouse model for the CHKB CMD and in muscle cells from CHKB CMD patients.
Important goals for these studies are to understand the mechanism underlying CHKB CMD and other muscular dystrophies that are caused by defects in the RyR, and to develop therapies to treat CHKB CMD and potentially other diseases (such as central core disease, and mitochondrial and other myopathies) that are linked to RyR defects.
What inspired you to study CMD?
I have a long-standing interest in mitochondria, cellular components that generate energy and are essential for muscle function. I developed an interest in CHKB CMD because one of the hallmarks for the disease is a severe defect in mitochondrial distribution. I was also inspired to study CHKB CMD by my first encounter with a CHKB CMD patient, which revealed the impact of the disease on the patient and their family, and the need to develop therapies to treat the disease.
What is your area of focus within the CMD field?
RyRs are present in one set of membranes within cells. However, there are widespread defects in other compartments in cells including mitochondria. I am interested in cross-talk between different membrane bound compartments within cells, and how defects in the RyR can lead to defects in the localization, morphology and function of mitochondria during disease progression.
This is an important area to study because defects in RyR and in mitochondria have been observed in a number of CMDs and indeed in muscle cells as they age. Thus, understanding the how defects in RyR affect mitochondria can contribute to our understanding of other CMDs and cellular processes.
Does your work have any potential implications for other disease fields?
Mutations in the RyR have been linked to heart diseases (e.g. sudden cardiac death, heart failure and arrhythmias) and cognitive dysfunction. Thus, our findings may impact each of these disease fields.
Why is it important that MDA continue to fund research in CMD?
Funding for CMD research from the government is severely limited at this time. With support from the MDA, there have been great discoveries including the genetic basis for multiple forms of CMD and approaches towards cures. The MDA has also brought new people into the field of CMD research, which fortifies the future of CMD research.
What do you feel people impacted by CMD can have the most hope about with respect to research right now?
In part through the efforts of the MDA, there has been an exponential increase in our understanding of CMD. We are in a better position than we have ever been in to develop methods for early diagnosis of CMD and potential therapies.
To learn more about how MDA research is accelerating treatments and cures for CMD, please visit mda.org.