Gary C. Sieck, Ph.D., studies the neural control of breathing muscles, including the diaphragm and airway smooth muscle.
Dr. Sieck has developed an extensive array of state-of-the-art physiological and biomedical engineering techniques to explore the interaction between motor neurons in the nervous system and the muscle fibers they innervate.
These techniques include confocal imaging of motor neurons in the spinal cord, biomechanical measurements of single muscle fiber contraction, determinations of contractile protein expression in muscle fibers, experimental and therapeutic manipulations of gene expression in motor neurons and muscle fibers, and exploration of cell signaling pathways mediating excitation-contraction coupling.
Dr. Sieck's research has been continuously funded by multiple grants from the National Institutes of Health for more than 30 years.
- Can functional recovery be enhanced after cervical spinal cord injury? Upper cervical spinal cord injury often results in complete or partial diaphragm muscle paralysis that may require ventilatory support for patients and is associated with higher morbidity and mortality rates. Clearly, it is important to understand how rhythmic diaphragm muscle activity can be restored in these spinal cord injury patients.
Dr. Sieck and his team have shown that functional recovery of diaphragm muscle activity is enhanced by promoting the effect of brain-derived neurotrophic factor (BDNF) acting through its high-affinity receptor (TrkB). For example, intrathecal BDNF treatment enhances functional recovery of rhythmic diaphragm muscle activity after spinal cord injury. Unfortunately, intrathecal BDNF treatment is associated with significant negative adverse effects that preclude its therapeutic use.
As an alternative, Dr. Sieck is exploring the use of locally implanted mesenchymal stem cells that are genetically engineering to produce BDNF. Dr. Sieck has also developed a novel targeted approach to increase TrkB expression in phrenic motoneurons using an adeno-associated virus and thereby promote functional recovery after spinal cord injury.
- How does the nervous system control contractile protein expression in muscle fibers? Dr. Sieck and his team are examining the trophic influence of motor neurons on contractile protein expression and ultimately the mechanical and energetic properties of muscle fibers. Dr. Sieck is exploring the mechanisms underlying muscle weakness in a variety of conditions, including neuromuscular disease (e.g., amyotrophic lateral sclerosis [ALS]), prolonged mechanical ventilation and aging (sarcopenia).
In particular, Dr. Sieck is examining the neural regulation of expression of different myosin heavy chain isoforms that form cross-bridges with actin during force generation and contraction. The expression of different myosin heavy chain isoforms also responds to conditions of altered use and thereby affects the mechanical and energetic properties of muscle fibers.
- Is calcium regulation altered in airway smooth muscle during asthma? Asthma is characterized by a hyper-reactivity of airway smooth muscles to neural agonists such as acetylcholine and histamine. The action of these agonists is mediated through an increase in intracellular calcium in airway smooth muscle cells.
Dr. Sieck is examining the mechanisms underlying calcium regulation in airway smooth muscle and how this regulation is altered by exposure to inflammatory cytokines.
Significance to patient care
The long-term goal of Dr. Sieck and his research team is to develop novel therapeutic approaches to counter the effects of neuromuscular disease or spinal cord injury on the neural control of the diaphragm muscle, and hyper-reactivity of airway smooth muscles in asthma and chronic obstructive pulmonary disease