Utilizes spontaneous and CRISPR/Cas9 generated mouse lines along with primary cell culture models to look at the molecular intersection between the motor neuron and heart phenotypes in mouse models of Spinal Muscular Atrophy with Respiratory Distress (SMARD).
Spinal Muscular Atrophy with Respiratory Distress (SMARD) is a very rare recessive form of Spinal Muscular Atrophy (SMA) that typically presents as acute respiratory failure between 6 weeks to 6 months of age followed by a progressive motor paralysis. Most patients die within 2-3 years, but some do plateau and live for many years with continuous respiratory, feeding and mobility support. Unfortunately, there is currently no cure.
A variety of different mutations in the Immunoglobulin mu-binding protein 2 (Ighmbp2) gene have been identified to be the cause of SMARD, but the mechanism of how these mutations result in this disease are still unknown. Since this is a recessive disease, that means that two mutant copies of the gene are required to be inherited…one from each parent.
In 1998, Greg Cox identified the first mouse model of this disease called nmd2J which is still the only model of SMARD utilized for research. The phenotype of these mice is consistent with the human patients. Unexpectedly, a genetic rescue of the nerves in this mouse model rescued the paralysis, but it also resulted in the development of a dilated cardiomyopathy (Maddatu TG et al. Hum Mol Genet 2004).
My work focuses on the molecular mechanism underlying both the motor neuron and cardiomyocyte phenotypes that develop as a result of mutations in Ighmbp2. Even though heart issues have not been identified in SMARD1 patients, the fear is that any treatment that fixes the paralysis and does not also treat the heart may produce the same fate for patients that we see in the mouse. The ultimate goal of this work is to identify therapeutic targets in both the heart and spinal cord….hopefully in both….to provide treatments to delay/stop cell death and expand the therapeutic window for genetic interventions.
Wild-type is the C57BL/6J inbred mouse strain, nmd2J is a homozygous mutant, and the rescued nmd2J is a homozygous mutant carrying a neuron-specific transgene of the Ighmbp2 gene to specifically rescue the paralysis. Femoral motor neuron cross-sections were imaged from 1 month old animals at 40x magnification. Whole heart longitudinal sections from 7-week-old animals were stained with Masson’s trichrome and imaged at 20x magnification. (Note: The rescued nmd2J nerve looks like the wild-type nerve).
The Jackson Laboratory
Adv: Dr. Greg Cox
The Jackson Laboratory
Adv: Dr. Susan Ackerman
Wake Forest University
Ph.D., Molecular Medicine & Translational Sciences
Adv: Dr. Colin Bishop
The University of Maine
B.S., Molecular & Cellular Biology
The College of the Atlantic
Adjunct course instructor
Penn State Cancer Institute
The University of Maine
Undergraduate research assistant
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