Our long-term objective is to provide an alternative source of motoneurons to reinnervate denervated muscles. Reinnervation would minimize and/or reverse the denervation-induced muscle wasting and dysfunction that is characteristic of many neuromuscular disorders and after central or peripheral nervous system trauma. We have shown that embryonic day 15 ventral spinal cord cells transplanted into peripheral nerve produce axons that form functional neuromuscular junctions with denervated muscles. In this proposal we aim to improve the strength of the reinnervated muscles by manipulation of the cells that are transplanted and the local neuromuscular environment. In adult Fischer rats, our Specific aims are to evaluate whether muscle reinnervation and function are improved by: 1) long-term delivery of pharmacological inhibitors to the transplant or muscles; 2) transplantation of embryonic cells of different ages; 3) long-term addition of trophic factors to the transplant; 4) combinations of these 3 treatments; 5) cell transplantation, then after a delay, the reintroduction of peripheral axons, a chronic denervation situation typical of peripheral nerve injuries. Outcomes measures will include survival of specific cell types by immunohistological characterization of the transplant; the number and diameter of myelinated axons in peripheral nerve; muscle reinnervation by retrograde fluorescent tracing, silver and acetylcholine esterase staining of axons and neuromuscular junctions; the number of reinnervated motor units judged by evoking distinct electromyographic steps in response to electrical stimulation of the transplant; muscle strength, fatigue resistance, fiber size and weight. These data will provide insights into the in vivo potential of embryonic ventral spinal cord cells to reinnervate adult muscle. Muscles with functional reinnervation can be excited artificially by electrical stimulation to potentially produce simple behaviors. This may improve the independence and quality of life of compromised individuals. Equally important, reinnervation may maintain muscle tissue, making it more receptive to renewed neural activity established by regeneration of peripheral or central axons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039098-06
Application #
6751621
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Porter, John D
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$374,246
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Liu, Yang; Grumbles, Robert M; Thomas, Christine K (2014) Electrical stimulation of transplanted motoneurons improves motor unit formation. J Neurophysiol 112:660-70
Grumbles, Robert M; Liu, Yang; Thomas, Christie M et al. (2013) Acute stimulation of transplanted neurons improves motoneuron survival, axon growth, and muscle reinnervation. J Neurotrauma 30:1062-9
Liu, Yang; Grumbles, Robert M; Thomas, Christine K (2013) Electrical stimulation of embryonic neurons for 1 hour improves axon regeneration and the number of reinnervated muscles that function. J Neuropathol Exp Neurol 72:697-707
Grumbles, Robert M; Almeida, Vania W; Casella, Gizelda T B et al. (2012) Motoneuron replacement for reinnervation of skeletal muscle in adult rats. J Neuropathol Exp Neurol 71:921-30
Casella, Gizelda T B; Almeida, Vania W; Grumbles, Robert M et al. (2010) Neurotrophic factors improve muscle reinnervation from embryonic neurons. Muscle Nerve 42:788-97
Grumbles, Robert M; Sesodia, Sanjay; Wood, Patrick M et al. (2009) Neurotrophic factors improve motoneuron survival and function of muscle reinnervated by embryonic neurons. J Neuropathol Exp Neurol 68:736-46
Grumbles, Robert M; Almeida, Vania W; Thomas, Christine K (2008) Embryonic neurons transplanted into the tibial nerve reinnervate muscle and reduce atrophy but NCAM expression persists. Neurol Res 30:183-9
Grumbles, Robert M; Casella, Gizelda T B; Rudinsky, Michelle J et al. (2007) Long-term delivery of FGF-6 changes the fiber type and fatigability of muscle reinnervated from embryonic neurons transplanted into adult rat peripheral nerve. J Neurosci Res 85:1933-42
Grumbles, R M; Casella, G T B; Rudinsky, M J et al. (2005) The immunophilin ligand FK506, but not the P38 kinase inhibitor SB203580, improves function of adult rat muscle reinnervated from transplants of embryonic neurons. Neuroscience 130:619-30
Baez, Juan Carlos; Gajavelli, Shyam; Thomas, Christine K et al. (2004) Embryonic cerebral cortex cells retain CNS phenotypes after transplantation into peripheral nerve. Exp Neurol 189:422-5

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