Multicellular living organisms and unmodified parts thereof and – Nonhuman animal
Reexamination Certificate
1999-02-12
2003-03-25
Baker, Annie-Marie (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
C800S003000, C424S009100, C435S004000, C435S006120
Reexamination Certificate
active
06538173
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention is related to the field of wound healing. More particularly, the invention is related to methods and compositions for enhancing wound healing in mammals.
BACKGROUND OF THE INVENTION
The biological response to tissue injury in higher organisms falls into two main categories: wound repair and regeneration (1). In amphibians, the form of wound healing seen is often epimorphic regeneration, where entire limbs can be reformed after amputation (1). In adult mammals, wound healing can involve wound repair or tissue regeneration, including the replacement of mature cells through cell proliferation (7) or replenishment of cells, but not organs, from immature stem cells (9, 11, 25). Complete wound healing, however, with perfect replacement of tissue and function, is typically not observed. Injuries to the central and peripheral nervous system, including optic nerve and spinal cord injuries, are especially refractory to healing. Thus, there is a need in the art for methods and compositions for enhancing wound healing in mammals.
SUMMARY OF THE INVENTION
It is an object of the invention to provide methods and compositions for use in healing wounds. These and other objects of the invention are provided by one or more of the embodiments described below.
One embodiment of the invention is a method of identifying a gene involved in enhanced wound healing. DNA microsatellite markers which can distinguish a first and a second mouse strain are identified. The first mouse strain is a healer mouse strain, and the second mouse strain is not a healer mouse strain. Microsatellite markers which segregate with enhanced wound healing in progeny of the first and second mouse strains are identified. A chromosomal locus which contains at least one gene involved in enhanced wound healing is thereby identified.
Still another embodiment of the invention is a method of treating a wound in a mammal. A reagent which specifically binds to an expression product of a gene whose expression is decreased in a healer mouse relative to a non-healer mouse is administered to a mammal with a wound. Expression of the gene is thereby decreased.
Even another embodiment of the invention is a method of treating a wound in a mammal. An expression product of a gene whose expression is increased after wounding in a healer mouse relative to expression of the gene after wounding in a non-healer mouse is administered to a mammal with a wound. The level of the expression product in the wound is thereby increased.
Yet another embodiment of the invention is a method of restoring function after nerve injury in a mammal. A reagent which specifically binds to an expression product of a gene whose expression is decreased after wounding in a healer mouse relative to expression of the gene after wounding in a non-healer mouse is administered to a mammal with a nerve injury. Expression of the gene is thereby decreased.
Another embodiment of the invention is a method of restoring function after nerve injury in a mammal. An expression product of a gene whose expression is increased after wounding in a healer mouse relative to expression of the gene after wounding in a non-healer mouse is administered to a mammal with a nerve injury. The level of the expression product in the wound is thereby increased.
Still another embodiment of the invention is a method of treating a wound in a mammal. A cell or cellular extract obtained from a healer mouse is administered to a mammal with a wound. Healing of the wound in the mammal is thereby enhanced.
Yet another embodiment of the invention is a method of treating a wound in a mammal. A cell in which expression of a wound healing gene has been altered is administered to a mammal with a wound. Healing of the wound in the mammal is thereby enhanced.
Even another embodiment of the invention is a healer mouse having at least one quantitative trait locus selected from the group consisting of the quantitative trait loci shown in Tables 2, 9 and 16. The healer mouse exhibits an enhanced healing response to a wound compared to a mouse which does not have the at least one chromosomal locus. The healer mouse is not an MRL mouse.
Yet another embodiment of the invention is a preparation comprising a fraction of an extract of a tissue of a healer mouse. The preparation alters a biological property of a model of wound healing.
Still another embodiment of the invention is a preparation comprising cells of a healer mouse. The preparation alters a biological property of a model of wound healing.
Another embodiment of the invention is a method of identifying a factor involved in enhanced wound healing. A model of wound healing is contacted with a preparation selected from the group consisting of serum, a fraction of serum, an extract of at least one healer mouse tissue, and a fraction of an extract of at least one healer mouse tissue. A property of the model of wound healing is assayed. A preparation which alters the property of the model of wound healing is identified as comprising a factor involved in enhanced wound healing.
Yet another embodiment of the invention is a method of screening test compounds for the ability to enhance wound healing. A healer model of wound healing is contacted with a test compound. The healer model comprises cells of a healer mouse. The effect of the test compound on a biological property associated with wound healing is measured in the healer model. A test compound which enhances the biological property of the healer model is identified as a potential factor for enhancing wound healing.
The present invention thus provides the art with a mammalian model of enhanced wound healing. The healer mouse described herein can be used, inter alia, to identify genes and gene products involved in enhanced wound healing and to provide methods and compositions for healing wounds, particularly wounds of the nervous system, in mammals.
REFERENCES:
patent: 97 33980 (1997-09-01), None
Lander & Kruglyak “Genetic Dissection of Complex Traits: Guidelines for Interpreting and Reporting Linkage Results” Nature Genetics, vol. 11, Nov. 1995, pp. 241-247.
Yu et al. “Differential Gene Expression in Healing Rat Corneal Epithelium” Investigative Ophthalmology and Visual Science, vol. 36, No. 10, 1995 pp. 1997-2007.
Fassler et al. “Differential Regulation of Fibulin, Tenascin-C, and Nidogen Expression During Wound Healing of Normal and Glucoccorticoid-Treated Mice” Experimental Cell Research, vol. 222, 1996, pp. 111-116.
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Dietrich et al. “A Genetic Map of the Mouse with 4,006 Simple Sequence Length Polymorphisms” Nature Genetics, vol. 7, 1994, pp. 220-224.
Hubner et al. “Differential Regulation of Pro-Inflammatory Cytokines During Wound Healing in Normal and Glucocorticoid-Treated Mice” Cytokine, vol. 8, No. 7, 1996, pp. 548-556.
Heber-Katz, Ellen, Abstract of NIH Grant No. 1 RO1 AI42395-01, obtained from the CRISP database available at <http://www.nih.gov>; Letter from Dorrette M. Finch, Director of Division of Research Documentation at NIH, stating that the abstract of NIH Grant No. 1 RO1 AI42395-01 was posted on the CRISP system on May 1, 1998.
McBrearty et al. “Genetic analysis of a mammalian wound-healing trait” Proc. Natl. Acad. Sci, USA vol. 95, pp. 11792-11797, Sep. 1998.
Clark et al. “A New Murine Model for Mammalian Wound Repair and Regeneration” Clinical Immunology and Immunopathology, vol. 88, No. 1, Jul. pp. 35-45, 1998.
Goss and Grimes “Epidermal Downgrowths in Regenerating Rabbit Ear Holes” J. Morph., 146: 533-542 (1975).
Baker Annie-Marie
Banner & Witcoff , Ltd.
The Wistar Institute
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