Transgenic mouse deficient in inducible nitric oxide synthase
AssigneesCornell Research Foundation, Inc., Merck & Co., Inc.
InventorsJohn MacMicking, Carl Nathan, John S. Mudgett
Life of this patent
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Abstract
The present invention provides an inducible nitric oxide synthase ("iNOS")-deficient transgenic mouse, novel replacement vectors designed for the disruption of the iNOS gene, embryonic stem (ES) cells which are singly allelic relative to the deficient iNOS locus, a host cell line or cell clone carrying a congenitally altered iNOS gene, and a method of producing such a transgenic mouse. The iNOS-deficient transgenic mice can be used to evaluate and/or test their susceptibility to infectious or tumorigenic challenge, autoimmunity, septic shock and inflammatory and allergic diseases.
Claims13
A transgenic mouse whose somatic and germ cells comprise a homozygous disrupted inducible nitric oxide synthase gene, said disruption sufficient to inhibit the production of nitric oxide by inducible nitric oxide synthase, said disrupted gene being introduced into said mouse or an ancestor of said mouse at an embryonic stage, wherein said mouse demonstrates an increased susceptibility to bacterial or viral infection and a decrease in susceptibility to sepsis as compared to a wild type mouse.
A transgenic mouse whose somatic and germ cells comprise a heterozygous disrupted inducible nitric oxide synthase gene, said disrupted gene being introduced into said mouse or an ancestor of said mouse at an embryonic stage, and wherein said disruption is sufficient to inhibit the production of nitric oxide by inducible nitric oxide synthase such that the mouse demonstrates a decreased susceptibility to sepsis as compared to a wild type mouse.
A method of producing a heterozygous mouse whose somatic and germ cells contain a gene coding for a disrupted mouse inducible nitric oxide synthase, comprising:
- (a) providing a gene coding for a disrupted mouse inducible nitric oxide synthase, said disruption having occurred at a level sufficient to prevent expression of mouse inducible nitric oxide synthase and/or production of nitric oxide by mouse inducible nitric oxide synthase;
- (b) introducing said gene into the blastocyst of an embryo;
- (c) transplanting the embryo into a pseudopregnant mouse and allowing said blastocyst to develop to term;
- (d) identifying a mouse which carries said disruption in one allele, said mouse exhibiting a decrease in susceptibility to sepsis as compared to wild type mice.
A method of producing a homozygous mouse whose somatic and germ cells contain a gene coding for a disrupted mouse inducible nitric oxide synthase, comprising:
- (a) providing a gene coding for a disrupted mouse inducible nitric oxide synthase, said disruption having occurred at a level sufficient to prevent expression of mouse inducible nitric oxide synthase and/or production of nitric oxide by mouse inducible nitric oxide synthase;
- (b) introducing said gene into a blastocyst;
- (c) transplanting said embryo into a pseudopregnant mouse and allowing said blastocyst to develop to term;
- (d) identifying a mouse which carries said disruption;
- (e) interbreeding said mouse of step (d) with a second mouse carrying said disruption;
- and
- (f) identifying a mouse which carries said disruption in both alleles, said mouse exhibiting a phenotype characterized by the substantial absence of expression of mouse inducible nitric oxide synthase and/or production of nitric oxide mouse by inducible nitric oxide synthase and by an increased susceptibility to bacterial or viral infectious agents, or a decreased susceptibility to sepsis.
Dependencies are inferred from the claim text.