Research Interests:
My laboratory studies normal and diseased craniofacial muscles, focusing on the extraocular muscles, and optic nerve injury and regeneration.
Ischemic optic neuropathy (ION) is a devastating ocular disease caused by disruption in arterial blood supply to the optic nerve head. This loss of oxygenation by interruption of the blood supply results in ischemic injury to the retinal ganglion cells and their axons, resulting in loss of visual field and decrease of visual acuity. The incidence of this disease is 2.3-10.3 per 100,000 in the US . The risk for development of ION on the fellow eye in affected patients is estimated to be 15-25%. There is no effective treatment for this condition. In addition, while the etiology of glaucoma is not well understood, there is increasing evidence that blood flow at the optic nerve head plays a role in development and progression of disease pathophysiology. Risk of disease is increased when ophthalmic artery flow rates decrease. We use a rodent model shown to produce a transient ischemia in the retina and optic nerve. These injuries result in significant but transient oxygen loss of the optic nerve, and by 5 months over half of the optic axons degenerate. Intranasal drug application produces almost instant drug delivery to brain structures with little evidence of systemic spread. It is non-invasive and easy to perform. This method was effective for the treatment of an animal model of focal brain ischemia. We are examining if intranasal administration of insulin growth factor-1 and/or erythropoietin can rescue retinal ganglion cells and optic axons that have been exposed to transient ischemia. We produce a transient ischemic injury to the retina and optic nerve in adult rats using a model of coagulopathy-induced ischemia followed by intranasal application of insulin growth factor-1 and/or erythropoietin. We subsequently will determine if intranasal IGF-1 and/or erythropoietin administration will rescue of ganglion cells and optic axon from injury and loss.
The extraocular muscles (EOM) move the eye in the orbit and are critical for normal binocular vision. The EOM differ from normal limb muscle in that they express a number of molecules normally seen only in developing or regenerating skeletal muscle. We made the novel observation that there is ongoing satellite cell division, myonuclear addition, and myofiber remodeling in adult uninjured extraocular muscles. Our main focus is directed at the following question: how do the unique properties expressed in the EOM relate to their preferential involvement or sparing in skeletal muscle diseases?
Duchenne muscular dystrophy (DMD) is a devastating disease for which there is currently no effective treatment. The clinical sparing of the EOM in DMD patients is an enigma. We are examining several aspects of the EOM that may play a role in this sparing. It may be that the myogenic precursor cell population in the EOM is different or more diverse than in limb skeletal muscles. We are studying the myogenic precursor population in the EOM to determine if these muscles contain more "multipotent precursor cells" than seen in limb skeletal muscles. It appears that there may be a unique population within the EOM that is both more "primitive" and also better able to survive injury than similar populations derived from limb skeletal muscle. In turn this leads to us to ask whether the myogenic precursor cells from EOM may be a better alternative for myoblast transfer for DMD than those cell derived from limb, which have been done with extremely limited success. In addition, EOM do not suffer changes seen in aging of limb skeletal muscle. The main hypothesis we are testing is that the myogenic precursor cell populations in the extraocular muscles are intrinsically different from those in limb muscle, and that these intrinsic differences may be, at least in part, responsible for the sparing of EOM in Duchenne muscular dystrophy and aging.
A second long term goal of the laboratory is to develop new treatments for strabismus, a condition caused by misalignment of the eyes due to EOM over- or under-action. We are testing the ability of novel immunotoxins to alter EOM strength for a duration sufficient to allow the brain to reorganize and improve binocular vision. The strategy is to link specific portions of various toxins to monoclonal antibodies to the nicotinic acetylcholine receptor, thereby targeting the myotoxicity to mature muscle only. One immunotoxin we are testing is ricin-mAb35. A single injection into the EOM resulted in long-lasting muscle weakness. We are the first demonstrate the effectiveness of myogenic growth factors in increasing muscle strength as a potential treatment of strabismus. Both single injections and sustained release of insulin growth factor or fibroblast growth factor 2 resulted in significantly increased muscle strength in treated EOMs. By developing better pharmacological drugs for agonist and antagonist pairs of EOM muscles, we hope to obtain a more effective, longer-lasting treatment for strabismic patients which does not require surgical intervention.
Selected Publications:
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
McLoon LK. Invited Editorial Focus. Focusing on fibrosis: Halofuginone-induced functional improvement in the mdx mouse model of Duchenne muscular dystrophy. Am J Physiol Heart Circ Physiol. ePublished February 29, 2008.
Christiansen SP, Anderson BC, McLoon LK. Botulinum toxin pretreatment augments the weakening effect of injection with ricin-mAb35 in rabbit extraocular muscle. J AAPOS. 11: Epublished February 6, 2008.
Antunes-Foschini RS, Miyashita D, Bicas HEA, McLoon LK. Activated satellite cells in medial rectus muscles from patients with strabismus. Invest. Ophthalmol. Vis. Sci. 49:215-220, 2008.
Anderson B, Christiansen SP, McLoon LK. Myogenic growth factors can decrease extraocular muscle force generation: A potential biological approach to the treatment of strabismus. Invest. Ophthalmol. Vis. Sci. 49: 221-229, 2008.
Harrison AR, Anderson BC, Thompson LV, McLoon LK. Myofiber length and three-dimensional localization of NMJs in normal and botulinum toxin treated adult extraocular muscles.
Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3594-601.
McLoon LK, Thorstenson KM, Solomon A, Lewis MP. Myogenic precursor cells in craniofacial muscles. Oral Dis. 2007 Mar;13(2):134-40.
Danylkova NO, Alcala SR, Pomeranz HD, McLoon LK. Neuroprotective effects of brimonidine treatment in a rodent model of ischemic optic neuropathy. Exp Eye Res. 2007 Feb;84(2):293-301.
McLoon LK, Anderson BC, Christiansen SP. Increasing muscle strength as a treatment for strabismus: sustained release of insulin-like growth factor-1 in rabbit extraocular muscle. J AAPOS. 2006 Oct;10(5):424-9.
Danylkova NO, Pomeranz HD, Alcala SR, McLoon LK. Histological and morphometric evaluation of transient retinal and optic nerve ischemia in rat. Brain Res. 2006 Jun 22;1096(1):20-9.
Anderson BC, Christiansen SP, Grandt S, Grange RW, McLoon LK. Increased extraocular muscle strength with direct injection of insulin-like growth factor-I. Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2461-7.
Harrison AR, McLoon LK. Reduction in touch sensitivity and hyperinnervation in vesicant-injured rabbit eyelid by direct injection of corticotropin releasing factor. Neurosci Lett. 2006 May 29;400:30-4.
Shinners MJ, Goding GS, McLoon LK. Effect of recurrent laryngeal nerve section on the laryngeal muscles of adult rabbits. Otolaryngol Head Neck Surg. 2006 Mar;134(3):413-8.
Christiansen SP, McLoon LK. The effect of resection on satellite cell activity in rabbit extraocular muscle. Invest Ophthalmol Vis Sci. 2006 Feb;47(2):605-13.
Ugalde I, Christiansen SP, McLoon LK. Botulinum toxin treatment of extraocular muscles in rabbits results in increased myofiber remodeling. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4114-20.
Current Graduate Students:
Sandra Alcala
(Neuroscience, University of Minnesota).
Kristen Thorstenson (Neuroscience, University of Minnesota). |
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