Government-Owned Inventions; Availability for Licensing: Mouse Models, 24499-24505 [2012-9775]

Agencies

• DEPARTMENT OF HEALTH AND HUMAN SERVICES
• National Institutes of Health

[Federal Register Volume 77, Number 79 (Tuesday, April 24, 2012)]
[Notices]
[Pages 24499-24505]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-9775]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing: Mouse 
Models

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

FOR FURTHER INFORMATION CONTACT: Licensing information for the 
technologies listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-

[[Page 24500]]

3804; telephone: 301-496-7057; fax: 301-402-0220.

Smad4 Knockout (Smad4\tm1Cxd\) Mouse Model for Developmental Biology 
Studies

    Description of Mouse: Smad4 knockout: Smad4 is essential for 
epiblast proliferation, egg cylinder formation and mesoderm induction 
in early embryogenesis.
    The TGF-beta-related superfamily plays an important role in 
multiple biological systems including embryogenesis. TGF-beta ligands 
activate specific receptors, which interact with specific Smad 
proteins, which in turn form a complex with a common partner, Smad4, 
that conveys the signal to downstream targets. Exon 8 of the Smad4 gene 
was disrupted using homologous recombination in embryonic stem cells. 
Exon 8 encodes the C-terminal domain of Smad4 that is essential for the 
formation of heteromeric complexes with the other Smads. Mice 
heterozygous for the Smad4 mutation are phenotypically normal. 
Homozygotes, however, die early in embryonic development (day E6.5-
8.5). Smad4 is required for three essential functions in early 
embryogenesis: epiblast proliferation, egg cylinder formation, and 
mesoderm induction.
    Potential Commercial Application: Study of developmental biology in 
conjunction with compounds.
    Development Status: Pre-clinical.
    Developer of Mouse: Chu-Xia Deng, Ph.D. (NIDDK).
    Relevant Publication: Yang X, et al. The tumor suppressor SMAD4/
DPC4 is essential for epiblast proliferation and mesoderm induction in 
mice. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3667-72. [PMID 
9520423].
    Intellectual Property: HHS Reference No. E-133-1999/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Charlene A. Sydnor, Ph.D.; 301-435-4689; 
sydnorc@mail.nih.gov.

Fgfr4 Knockout Mouse Model for Respiratory System Studies

    Description of Mouse: FGFR4 knockout: Lung alveoli fail to develop 
normally in double mutant with FGFR4 and FGFR3 knockouts.
    The fibroblast growth factor receptor 4 (fgfr-4) gene was 
inactivated by targeted disruption and homozygous recombination to 
study its possible role in lung development. FGFR-4 is expressed in 
postnatal lung, and FGFR-4 null mice have no obvious abnormalities. 
However, mice that are doubly homozygous for targeted disruptions of 
FGFR3 and FGFR4 display novel phenotypes, including pronounced dwarfism 
and lung abnormalities. The lungs of the double knockout mice are 
normal at birth, but they fail to develop secondary septae that delimit 
alveoli and increase the surface area of the lung. Although lung 
function is impaired, the double homozygous knockout mice are viable 
but sickly.
    Potential Commercial Application: Model for the study of 
respiratory system and potential treatments.
    Development Status: Pre-clinical.
    Developer of Mouse: Chu-Xia Deng, Ph.D. (NIDDK).
    Relevant Publication: Weinstein M, et al. FGFR-3 and FGFR-4 
function cooperatively to direct alveogenesis in the murine lung. 
Development. 1998 Sep;125(18):3615-23. [PMID 9716527].
    Intellectual Property: HHS Reference No. E-125-2000/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Charlene A. Sydnor, Ph.D.; 301-435-4689; 
sydnorc@mail.nih.gov.

M5 Muscarinic Receptor Knockout (Chrm5\tm1Jwe\) Mouse Model for 
Neurological Studies

    Description of Mouse: M5 muscarinic receptor knockout: Deficiency 
of M5Rs reduces drug-seeking behavior.
    The five Muscarinic Acetylcholine (ACh) receptors are G-protein 
coupled receptors (M1R-M5R). M1R, M3R and M5R selectively couple to Gq/
G11; M2R and M4R selectively couple to Gi/Go. M5R knockout mice are 
viable and fertile, and have no major morphological abnormalities.
    M5 muscarinic ACh receptors are located in the central nervous 
system and may contribute to the cognitive-enhancing effects of ACh. 
M5R knockout mice show deficits in two hippocampus-dependent cognitive 
tasks, and exhibit reduced cerebral blood flow in the cerebral cortex 
and hippocampus, consistent with the observation that M5Rs mediate ACh-
mediated dilation of cerebral blood vessels. M5R agonists or agonists 
for mixed M1/M5 receptors may be effective in the treatment of 
Alzheimer's disease and related memory disorders. The M5R knockout 
mutation also appears to exert a stabilizing effect on sensorimotor 
gating in intact mice, which is decreased in schizophrenia. Analysis of 
M5R knockout mice also has shown that the lack of M5Rs reduces drug-
seeking behavior.
    Potential Commercial Application: Mouse model for use in 
neurological studies.
    Development Stage: Pre-clinical.
    Developer of Mouse: J[uuml]rgen Wess, Ph.D. (NIDDK).
    Relevant Publication: Yamada M, et al. Cholinergic dilation of 
cerebral blood vessels is abolished in M(5) muscarinic acetylcholine 
receptor knockout mice. Proc Natl Acad Sci U S A. 2001 Nov 
20;98(24):14096-101. [PMID 11707605].
    Intellectual Property: HHS Reference No. E-110-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Charlene A. Sydnor, Ph.D.; 301-435-4689; 
sydnorc@mail.nih.gov.

Stat5a LoxP/Stat5b LoxP (Stat5a/Stat5b\tm2Mam\) Mouse Model for 
Mammopoietic and Lactogenic Signaling Studies

    Description of Mouse: Conditional knockout of Stat5a and Stat5b: 
Combined deletion of conserved Stat5a and Stat5b in mammary epithelium 
at different times during pregnancy reveal multiple distinct functions.
    The signal transducer and activator of transcription (STAT) family 
of transcription factors conveys signals from membrane receptors to the 
nucleus, where they activate diverse genetic programs. Stat5a and 
Stat5b are highly conserved proteins that are activated by many 
cytokines, erythropoietin, prolactin and growth hormone. Despite their 
similarities, they have many unique functions. Stat5a deficiency 
results in the loss of prolactin-dependent mammary gland development, 
but does not affect body growth. Inactivation of Stat5b does not 
adversely affect mammary development and function, but leads to severe 
growth retardation. To study the effects of combined deficiency of Stat 
5a and 5b before and during pregnancy, loxP was added to the ends of a 
DNA fragment that contains the two genes which are located within a 
stretch of 110 kb on chromosome 11 in a head to head orientation with 
no other genes between them. The loxP-flanked fragment was introduced 
into the genome using homologous recombination, and deleted using two 
transgenic lines expressing Cre in mammary epithelium at different 
times. Deletion of Stat 5 before pregnancy prevents epithelial 
proliferation. Ductal characteristics are retained but differentiation 
into secretory alveoli does not occur. When deletion of Stat5 occurs 
late in pregnancy after differentiation has started, differentiation is 
halted and premature death occurs.

[[Page 24501]]

    Potential Commercial Application: Mouse model to study mammopoietic 
and lactogenic signaling.
    Development Stage: Pre-clinical.
    Developer of Mouse: Lothar Hennighausen, Ph.D. (NIDDK).
    Relevant Publication: Cui Y, et al. Inactivation of Stat5 in mouse 
mammary epithelium during pregnancy reveals distinct functions in cell 
proliferation, survival, and differentiation. Mol Cell Biol. 2004 
Sep;24(18):8037-47. [PMID 15340066].
    Intellectual Property: HHS Reference No. E-114-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Suryanarayana (Sury) Vepa, Ph.D., J.D.; 301-435-
5020; vepas@mail.nih.gov.

Stat5a Knockout (Stat5a\tm1Mam\) Mouse Model for Mammopoietic and 
Lactogenic Signaling Studies

    Description of Mouse: Stat5a Knockout: Stat5a deficiency results in 
the loss of prolactin-dependent mammary gland development and 
lactogenesis.
    Prolactin induces mammary gland development and lactogenesis. 
Binding of Prolactin to its receptor leads to the phosphorylation and 
activation of STAT (signal transducers and activators of transcription) 
proteins. Two Stat proteins, Stat5a and Stat5b, are expressed in 
mammary tissues during pregnancy. Stat5a null mice developed normally, 
and were indistinguishable from hemizygous and wild-type littermates in 
size, weight and fertility. Mammary lobulo-alveolar outgrowth during 
pregnancy was reduced and females failed to lactate after parturition. 
Stat5b, despite 96% similarity to Stat5a, could not compensate for the 
loss of Stat5a. Stat5a is the principal and obligate mediator of 
mammopoietic and lactogenic signaling.
    Potential Commercial Application: Mouse model to study mammopoietic 
and lactogenic signaling.
    Development Stage: Pre-clinical.
    Developer of Mouse: Lothar Hennighausen, Ph.D. (NIDDK).
    Relevant Publication: Liu X, et al. Stat5a is mandatory for adult 
mammary gland development and lactogenesis. Genes Dev. 1997 Jan 
15;11(2):179-86. [PMID 9009201].
    Intellectual Property: HHS Reference No. E-116-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Suryanarayana (Sury) Vepa, Ph.D., J.D.; 301-435-
5020; vepas@mail.nih.gov.

Gs Alpha LoxP (Gnas\tm1Lsw\) Mouse Model for Metabolism Studies

    Description of Mouse: Generation of a floxed Gnsa gene for the G-
protein Gs alpha (Gs[alpha]) for the construction 
of conditional knockout mice.
    The heterotrimeric G protein Gs[alpha] couples many 
receptors to adenylyl cyclase and is essential for hormone-stimulated 
cAMP generation. Previous mouse models with germ-line mutations in 
Gnas, the gene that encodes Gs[alpha] had limited usefulness 
in trying to decipher the role of Gs[alpha] pathways in 
specific tissues since only heterozygotes were viable and could be 
analyzed. Analysis was further complicated by the fact that 
Gs[alpha] is imprinted expressed in many metabolically 
active tissues.
    Gs[alpha]-floxed mice were generated so that the 
metabolic effects of Gs[alpha] deficiency could be examined 
in specific tissues. Exon1, which is specific for Gs[alpha], 
was surrounded with loxP recombination sites. Liver-specific knockouts 
of Gs[alpha] were obtained by mating the 
Gs[alpha]-floxed mice with albumin promoter-Cre-transgenic 
mice. Gs[alpha] exon1 was efficiently deleted. These mice 
have been used successfully to generate other tissue-specfic 
Gs[alpha] knockout mice.
    Potential Commercial Application: Mouse model to study metabolism.
    Development Stage: Pre-clinical.
    Developer of Mouse: Lee Weinstein, M.D. (NIDDK).
    Relevant Publication: Chen M, et al. Increased glucose tolerance 
and reduced adiposity in the absence of fasting hypoglycemia in mice 
with liver-specific Gs alpha deficiency. J Clin Invest. 2005 
Nov;115(11):3217-27. [PMID 16239968].
    Intellectual Property: HHS Reference No. E-117-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Suryanarayana (Sury) Vepa, Ph.D., J.D.; 301-435-
5020; vepas@mail.nih.gov.

Sirt6 LoxP (Sirt6\tm1.1Cxd\) Mouse Model for Liver Studies

    Description of Mouse: Generation of floxed Sirtuin 6 for the 
construction of conditional knockout mice.
    The Sirtuins (Sirt1-7), a family of seven proteins related to yeast 
Sir2, are histone deacetylases that regulate many critical biological 
processes including genomic stability, adaptation to calorie 
restriction and aging. Mice with a targeted disruption of Sirt6 had 
very low levels of blood glucose (and paradoxically, low insulin 
levels) and died shortly after weaning. Hypoglycemia, attributed to 
increased sensitivity to insulin, was the major cause for lethality.
    Because of the post-weaning mortality of Sirt6 null mice, liver-
specific Sirt6 conditional knockout mice were constructed using Cre-Lox 
technology to study the effects on glucose and lipid metabolism. 
Hepatic-specific Sirt6 deficient mice exhibited increased glycolysis 
and triglyceride synthesis, resulting in the development of fatty 
liver. Sirt6 is a potential therapeutic target for treating fatty liver 
disease, the most common cause of liver dysfunction.
    Potential Commercial Application: Mouse model to study the liver.
    Development Stage: Pre-clinical.
    Developer of Mouse: Chuxia Deng, Ph.D. (NIDDK).
    Relevant Publication: Kim HS, et al. Hepatic-specific disruption of 
SIRT6 in mice results in fatty liver formation due to enhanced 
glycolysis and triglyceride synthesis. Cell Metab. 2010 Sep 
8;12(3):224-36. [PMID 20816089].
    Intellectual Property: HHS Reference No. E-121-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Lauren Nguyen-Antczak, Ph.D., J.D.; 301-435-
4074; Lauren.Nguyen-Antczak@nih.gov.

Sirt1 LoxP (Sirt1\tm1Cxd\) Mouse Model for Metabolism and Hepatology 
Studies

    Description of Mouse: Generation of floxed Sirtuin 1 Exon5-Exon6 
for the construction of conditional knockout mice.
    Sirtuin 1 (Sirt1), a homolog of yeast Sir 2, is an NAD-dependent 
histone and protein deacetylase. It has a wide range of biological 
functions, ranging from DNA damage repair to effects on glucose 
metabolism. Sirt1 null mice die before birth due to chromosomal 
aberrations and impaired DNA damage repair. Sirt1 is thought to affect 
energy metabolism, but the mechanism remains poorly understood. In 
order to study tissue-specific metabolic effects of Sirt1, floxed Sirt1 
was constructed so that exons 5 and 6 would be deleted using the Cre-
Lox strategy. In contrast to a previously reported deletion of Sirt1 
exon4, no truncated (and potentially active) Sirt1 forms were detected 
when exons 5 and 6 were deleted.
    Hepatic exon 5-6 null Sirt1 mice were generated when Floxed Sirt1 
exon 5 and 6 mice were mated with mice that expressed the Cre-
recombinase in liver. The hepatic exon 5-6 null Sirt1 mice developed 
fatty liver under normal feeding conditions. This was accompanied by 
increased expression of the carbohydrate responsive element binding 
protein, which is a major

[[Page 24502]]

regulator of lipid synthesis. Sirt1-deficient liver also has an 
impaired insulin response, primarily due to reduced phosphorylation of 
the serine-threonine kinase Akt in the presence of insulin.
    Potential Commercial Application: Mouse model to study metabolism 
and hepatology.
    Development Stage: Pre-clinical.
    Developer of Mouse: Chuxia Deng, Ph.D. (NIDDK).
    Relevant Publications:

1. Wang RH, et al. Liver steatosis and increased ChREBP expression in 
mice carrying a liver specific SIRT1 null mutation under a normal 
feeding condition. Int J Biol Sci. 2010 Nov 16;6(7):682-90. [PMID 
21103071].
2. Wang RH, et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt 
signaling and results in hyperglycemia, oxidative damage, and insulin 
resistance. J Clin Invest. 2011 Nov 1;121(11):4477-90. [PMID 21965330].

    Intellectual Property: HHS Reference No. E-122-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Lauren Nguyen-Antczak, Ph.D., J.D.; 301-435-
4074; Lauren.Nguyen-Antczak@nih.gov.

Fgfr3 Knockout Mouse Model for Developmental Biology Studies

    Description of Mouse: FGFR3 knockout. Complete knockout of the 
FGFR3 gene, the gene in which missense mutants cause short statue 
achondroplasia, fails to restrain cartilage growth at the bone growth 
plate, allowing bones to elongate excessively but fail to ossify.
    Endochondral ossification is a major mode of bone formation. 
Cartilage proliferates, undergoes hypertrophy, begins to calcify, 
undergoes a program of cell death, and is replaced by osteoblasts. 
Fibroblast Growth Factor Receptor 3 (FGFR3) is expressed in cartilage 
rudiments of a wide variety of bones, and dominant missense mutations 
in the human FGFR3 gene cause achondroplasia, a common form of human 
dwarfism characterized by minimal proliferation of the growth plate 
cartilage in long bones. To determine the effect of complete absence of 
FGFR3 on bone development in mice, targeted disruption of the FGFR3 
gene was accomplished by homologous recombination in embryonic stem 
cells. Remarkably, the vertebral column and long bones of FGFR3 null 
mice were extremely long, suggesting that in normal development, FGFR3 
restrains cartilage promotion and limits bone elongation so that the 
endochondral ossification program can proceed. Restraint of cartilage 
growth by FGFR3 provides a plausible explanation for the role of FGFR3 
missense mutations in human achondroplastic dwarfs.
    Potential Commercial Application: Mouse model to study 
developmental biology.
    Development Stage: Pre-clinical.
    Developer of Mouse: Chuxia Deng, Ph.D. (NIDDK).
    Relevant Publication: Deng C, et al. Fibroblast growth factor 
receptor 3 is a negative regulator of bone growth. Cell. 1996 Mar 
22;84(6):911-21. [PMID 8601314]
    Intellectual Property: HHS Reference No. E-123-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Lauren Nguyen-Antczak, Ph.D., J.D.; 301-435-
4074; Lauren.Nguyen-Antczak@nih.gov.

Fgfr2 Knockout (Fgfr2 \tm1Cxd\) Mouse Model for Developmental Biology 
Studies

    Description of Mouse: FGFR2 knockout is an embryonic lethal 
mutation and blocks limb bud initiation.
    Fibroblast Growth Factor Receptor 2 (FGFR2) is a high affinity 
receptor for several members of the FGF family. The FGFR2 gene was 
inactivated by deleting the entire immunoglobulin-like domain of the 
receptor which is critical for FGF binding and FGFR2 activity. Embryos 
that lack this domain die at E10-11.5 owing to a failure in 
chorioallantoic fusion or placental formation. The deletion also blocks 
limb bud initiation, establishing FGFR2 as the major receptor that 
mediates FGF signals during limb induction.
    Potential Commercial Application: Mouse model to study 
developmental biology.
    Development Stage: Pre-clinical.
    Developer of Mouse: Chuxia Deng, Ph.D. (NIDDK).
    Relevant Publication: Xu X, et al. Fibroblast growth factor 
receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and 
FGF10 is essential for limb induction. Development. 1998 
Feb;125(4):753-65. [PMID 9435295].
    Intellectual Property: HHS Reference No. E-124-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Lauren Nguyen-Antczak, Ph.D., J.D.; 301-435-
4074; Lauren.Nguyen-Antczak@nih.gov.

Alb-tTA (Tg(Alb1-tTA)3123Lng) Mouse Model for Liver Function Studies

    Description of Mouse: Tetracycline-responsive transcriptional 
activator driven by the liver-specific mouse albumin promoter (Alb-
tTA).
    The E. Coli tetracycline operon regulatory system was used to 
generate a liver-specific transcription activation system that was 
inhibited by tetracycline. The transcription activator was a fused 
protein consisting of a tetracycline repressor gene (tetR) that was 
only active in the presence of tetracycline and a herpes simplex virus 
protein (VP-16) transcription activating domain. Transcription was 
induced only in the absence of tetracycline (Tet-Off). A liver-specific 
promoter such as mouse albumin determined that the tetracycline-
regulated transcriptional activator (tTA) would be expressed 
specifically in liver. To study the effect of the transcription 
activator on a target gene (for example, Simian Virus 40 (SV4) large 
tumor (T) antigen (TAg)) specifically in liver, Alb-tTA mice were mated 
with transgenic mice in which the Target gene (TAg) was controlled by 
the E. Coli Tetracycline Operator (Tet-O). In this example, TAg was 
expressed in hepatocytes in the absence of Tetracycline, leading to 
hepatoma formation. When the mice were treated with tetracycline, TAg 
was not expressed and hepatomas did not form.
    Potential Commercial Application: Mouse model to liver function.
    Development Stage: Pre-clinical.
    Developer of Mouse: T. Jake Liang, M.D. (NIDDK).
    Relevant Publication: Manickan E, et al. Conditional liver-specific 
expression of simian virus 40 T antigen leads to regulatable 
development of hepatic neoplasm in transgenic mice. J Biol Chem. 2001 
Apr 27;276(17):13989-94. [PMID 11278564]
    Intellectual Property: HHS Reference No. E-125-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Lauren Nguyen-Antczak, Ph.D., J.D.; 301-435-
4074; Lauren.Nguyen-Antczak@nih.gov.

MUP-tTA Mouse Model for Liver Function Studies

    Description of Mouse: Tetracycline-responsive transcriptional 
activator driven by the liver-specific mouse major urinary protein 
promoter (MUP-tTA).
    The E. Coli tetracycline operon regulatory system was used to 
generate a liver-specific transcription activation system that was 
inhibited by tetracycline. The transcription activator was a fused 
protein consisting of a

[[Page 24503]]

tetracycline repressor gene (tetR) that was only active in the presence 
of tetracycline and a herpes simplex virus protein (VP-16) 
transcription activating domain (Tet-Off). Transcription was induced 
only in the absence of tetracycline (Tet-Off). A liver-specific 
promoter such as the mouse major urinary protein (MUP) promoter 
determined that the tetracycline-regulated transcriptional activator 
(tTA) would be expressed specifically in liver. To study the effect of 
the transcription activator on a target gene (for example, beta-
galactosidase, LacZ) specifically in liver, MUP-tTA mice would be mated 
with transgenic mice in which the TAg Target gene was controlled by the 
E. Coli Tetracycline Operator (Tet-O). The Tet technology may require a 
separate license.
    Potential Commercial Application: Mouse model to study liver 
function.
    Development Stage: Pre-clinical.
    Developer of Mouse: T. Jake Liang, M.D. (NIDDK).
    Relevant Publication: Manickan E, et al. Conditional liver-specific 
expression of simian virus 40 T antigen leads to regulatable 
development of hepatic neoplasm in transgenic mice. J Biol Chem. 2001 
Apr 27;276(17):13989-94. [PMID 11278564]
    Intellectual Property: HHS Reference No. E-126-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Lauren Nguyen-Antczak, Ph.D., J.D.; 301-435-
4074; Lauren.Nguyen-Antczak@nih.gov.

mEpoR Knockout/Tg(hEpoR) Mouse Model for Anemia and Renal Function 
Studies

    Description of Mouse: mEpoR-/-hEpoR+: The mouse Erythropoietin 
Receptor knockout that contains a human Erythropoietin Receptor 
transgene can be used to define the potency of recombinant 
erythropoietin preparations used to treat anemia associated with 
chronic kidney disease.
    Erythropoietin, acting by binding to Erythropoietin receptors 
(EpoR) on erythroid progenitor cells, is required for erythropoiesis. 
Absence of erythropoietin or the EpoR in mice interrupts erythropoiesis 
in the fetal liver and results in death at embryonic day 13.5. An 80-kb 
human EpoR transgene bred onto a mouse EpoR null background (provided 
by F. Constantini of Columbia University) restored effective 
erythropoiesis in the EpoR null mouse. Erythropoietin preparations made 
utilizing recombinant DNA technology are used in the treatment of 
anemia in chronic kidney disease and other critical illnesses. The 
mouse EpoR null mouse containing the human EpoR transgene can be used 
to define the potency of erythropoietin preparation in humans.
    Potential Commercial Applications: Model for study of anemia and 
renal function and possible drug screening.
    Developer of Mouse: Constance Noguchi, Ph.D. (NIDDK).
    Relevant Publication: Yu X, et al. The human erythropoietin 
receptor gene rescues erythropoiesis and developmental defects in the 
erythropoietin receptor null mouse. Blood. 2001 Jul 15;98(2):475-7. 
[PMID 11435319].
    Intellectual Property: HHS Reference No. E-127-2001/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Jennifer S. Wong; 301-435-4633; 
wongje@mail.nih.gov.

Sirt3 Knockout (Sirt3\tm1.1Cxd\) Mouse Model for Cardiology and 
Metabolism Studies

    Description of Mouse: Sirt3 knockout: Sirt3 is a mitochondrial-
localized tumor suppressor that maintains mitochondrial integrity and 
metabolism during stress. Sirt3 is a mitochondrial protein that is a 
member of the Sirtuin family of NAD-dependent protein deacetylases. 
Sirt3(-/-) mice are phenotypically normal, but exhibit many proteins 
whose acetylation is increased. They generate more reactive oxygen 
species and are more susceptible to mammary tumors than normal mice. 
Sirt3 is inactivated in a large percentage of human breast and ovarian 
cancers, suggesting that Sirt3 may be a mitochondria-localized tumor 
suppressor by maintaining mitochondrial integrity and efficient 
oxidative metabolism.
    Potential Commercial Applications: Cardiology, Metabolism.
    Developer of Mouse: Chuxia Deng, Ph.D. (NIDDK).
    Relevant Publication: Kim HS, et al. SIRT3 is a mitochondria-
localized tumor suppressor required for maintenance of mitochondrial 
integrity and metabolism during stress. Cancer Cell. 2010 Jan 
19;17(1):41-52. [PMID 20129246].
    Intellectual Property: HHS Reference No. E-119-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Jennifer S. Wong; 301-435-4633; 
wongje@mail.nih.gov.

Sirt1 Knockout (Sirt1\tm1.1Cxd\) Mouse Model for Oncology and 
Metabolism Studies

    Description of Mouse: Sirt1 knockout: Sirt1, a protein deacetylase, 
is a tumor suppressor that promotes genome stability and regulates 
proteins involved in energy metabolism.
    Yeast Sir2, a nicotinamide adenine dinucleotide (NAD)-dependent 
protein deacetylase, has been implicated in chromatin silencing, 
longevity and genome stability. Mammals contain a family of related 
deacetylases, the sirtuins, of which 7 have been identified. Sirt1 is 
the closest mammalian orthologue of yeast Sir 2. The Sirt1 gene in mice 
was disrupted by homologous recombination in embryonic stem cells. The 
majority of Sirt1 (-/-) embryos die between E9.5 and E14.5, displaying 
altered histone modification, increased chromosomal aberrations, and 
impaired DNA damage repair. Tumor formation was increased in mutant 
tissues in Sirt1(+/-): p53(+/-) double heterozygotes, indicating that 
full levels of Sirt1 are necessary for tumor suppression. Tumorigenesis 
is reduced by treatment with the polyphenol, resveratrol, which 
activates Sirt1. Sirt1 may act as a tumor suppressor by promoting DNA 
damage repair and maintaining genome integrity. Sirt1also is involved 
in the regulation of proteins involved in energy metabolism, and 
components of the circadian clock.
    Potential Commercial Applications: Oncology, Metabolism.
    Developer of Mouse: Chuxia Deng, Ph.D. (NIDDK).
    Relevant Publication: Wang RH, et al. Impaired DNA damage response, 
genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer 
Cell. 2008 Oct 7;14(4):312-23. [PMID 18835033]
    Intellectual Property: HHS Reference No. E-120-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Jennifer S. Wong; 301-435-4633; 
wongje@mail.nih.gov.

Stat1LoxP (Stat1\tm1Mam\) Mouse Model for Oncology and Immunology 
Studies

    Description of Mouse: Selective inactivation of Stat1 in mammary 
cells indicates that its effect as a tumor suppressor in breast is 
direct.
    STAT1 is considered a tumor suppressor, but it is not known if this 
effect occurs directly in mammary cells or secondarily by disrupting 
interferon signaling through the JAK/STAT1 pathway to induce immune 
responses. ERBB2/neu-induced breast cancer appeared sooner in mice 
lacking STAT1 only in mammary cells than in wild-type mice, indicating 
that STAT1 tumor suppression was intrinsic to mammary cells and not 
secondary to an induced immune response.

[[Page 24504]]

    Potential Commercial Applications: Oncology, Immunology.
    Developer of Mouse: Lothar Hennighausen, Ph.D. (NIDDK).
    Relevant Publication: Klover PJ, et al. Loss of STAT1 from mouse 
mammary epithelium results in an increased Neu-induced tumor burden. 
Neoplasia. 2010 Nov;12(11):899-905. [PMID 21076615].
    Intellectual Property: HHS Reference No. E-111-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Mojdeh Bahar, J.D., CLP; 301-435-2950; 
baharm@mail.nih.gov.

Tg(Wap-cre)11738Mam Mouse Model for Developmental Biology Studies

    Description of Mouse: Cre-recombinase under the control of the whey 
acidic acid protein was only detected in alveolar epithelial cells of 
mammary tissue during lactation, and transcription occurred at all 
stages of mammary development.
    The Cre recombinase from bacteriophage P1 excises intervening DNA 
sequences located between two unidirectional lox sites positioned on 
the same linear DNA segment, leaving one lox site behind. Through 
insertion of lox sites via homologous recombination into the gene of 
interest and targeting Cre recombinase expression to a specific cell 
type using a tissue-specific promoter, it is possible to introduce 
predetermined deletions into the mammalian genome. To delete genes 
specifically from mammary gland, transgenic mice were created carrying 
the Cre gene under the control of the whey acidic protein (WAP) gene 
promoter. Expression of WAP-Cre was only detected in alveolar 
epithelial cells of mammary tissue during lactation. Recombination 
mediated by Cre under control of the WAP gene promoter was largely 
restricted to the mammary gland but occasionally was observed in the 
brain. High-level transcriptional activity of WAP-based transgenes can 
be obtained at every stage of mammary development.
    Potential Commercial Application: Developmental Biology.
    Developer of Mouse: Lothar Hennighausen, Ph.D. (NIDDK).
    Relevant Publication: Wagner KU, et al. Cre-mediated gene deletion 
in the mammary gland. Nucleic Acids Res. 1997 Nov 1;25(21):4323-30. 
[PMID 9336464].
    Intellectual Property: HHS Reference No. E-112-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Mojdeh Bahar, J.D., CLP; 301-435-2950; 
baharm@mail.nih.gov.

Tg(MMTV-Cre)Mam Mouse Model for Developmental Biology, 
Hepatology, and Oncology Studies

    Description of Mouse: Cre-recombinase under the control of mouse 
mammary tumor virus long terminal repeat (MMTV) was expressed in the 
salivary gland and mammary epithelial cells of adult mice, and induced 
recombination in all tissues.
    The Cre recombinase from bacteriophage P1 excises intervening DNA 
sequences located between two unidirectional lox sites positioned on 
the same linear DNA segment, leaving one lox site behind. Through 
insertion of lox sites via homologous recombination into the gene of 
interest and targeting Cre recombinase expression to a specific cell 
type using a tissue-specific promoter, it is possible to introduce 
predetermined deletions into the mammalian genome. To delete genes 
specifically from mammary gland, transgenic mice were created carrying 
the Cre gene under the control of the mouse mammary tumor virus (MMTV) 
long terminal repeat (LTR). In adult MMTV-Cre mice, expression of the 
transgene was confined to striated ductal cells of the salivary gland 
and mammary epithelial cells in virgin and lactating mice. In contrast 
to WAP-Cre, however, Cre expression under control of the MMTV LR 
resulted in recombination in all tissues.
    Potential Commercial Applications: Developmental Biology, 
Hepatology, Oncology.
    Developer of Mouse: Lothar Hennighausen, Ph.D. (NIDDK).
    Relevant Publication: Wagner KU, et al. Cre-mediated gene deletion 
in the mammary gland. Nucleic Acids Res. 1997 Nov 1;25(21):4323-30. 
[PMID 9336464].
    Intellectual Property: HHS Reference No. E-113-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Mojdeh Bahar, J.D., CLP; 301-435-2950; 
baharm@mail.nih.gov.

Bcl-x LoxP (Bcl2l1\tm1.1Mam\) Mouse Model for Developmental Biology 
Studies

    Description of Mouse: Floxed Bcl-x: Conditional knockout of pro-
survival Bcl-x in primordial germ cells was used to study the balance 
between pro-apoptotic Bax during embryogenesis.
    Bcl-x is a pro-survival protein that opposes the pro-apoptotic 
action of Bax which interacts with mitochondria to activate the caspase 
9 pathway. Mice in which the Bcl-x gene is inactivated die at E12.5. To 
be able to study lineage-specific activities of Bcl-x at different 
stages of development, the Cre-LoxP recombination system was used. 
Homologous recombination was used to flank the promoter, exon1, and 
major coding exon2 of the Bcl-x gene with loxP sites. The targeted 
allele contained a loxP flanked (or floxed) neomycin cassette in the 
Bcl-x promoter, and an additional loxP site in intron 2. Floxed Bcl-x 
has been used to study the balance between Bcl-x and Bax in primordial 
germ cells that undergo controlled levels of cell reduction due to 
apoptosis, the induction of hemolytic anemia and splenomegaly following 
conditional deletion of the Bcl-x gene from erythroid cells, the 
protection of hepatocytes from apoptosis and ensuing fibrotic response 
by Bcl-x, and the demonstration that Bcl-x is critical for the survival 
of dendritic cells, important regulators of immune function.
    Potential Commercial Application: Developmental Biology.
    Developer of Mouse: Lothar Hennighausen, Ph.D. (NIDDK).
    Relevant Publication: Rucker EB 3rd, et al. Bcl-x and Bax regulate 
mouse primordial germ cell survival and apoptosis during embryogenesis. 
Mol Endocrinol. 2000 Jul;14(7):1038-52. [PMID 10894153].
    Intellectual Property: HHS Reference No. E-115-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Mojdeh Bahar, J.D., CLP; 301-435-2950; 
baharm@mail.nih.gov.

UTX LoxP Mouse Model for Oncology Research

    Description of Mouse: UTX-flox. Conditional knockout mice for the 
histone demethylase UTX (Kdm6a) conditional knockout will help 
understand its role as a tumor suppressor.
    Di- and tri-methylations on histone H3 lysine 27 (H3K27me2 and 
H3K27me3) are epigenetic marks for gene repression. UTX (ubiquitously 
transcribed X chromosome protein), also known as Kdm6a (lysine (K)-
specific demethylase 6a) is a histone demethylase that specifically 
removes H3K27me2 and H3K27me3. UTX knockout mice are embryonic lethal, 
so we have generated UTX conditional knockout mice (UTX-flox) in which 
exon 24 is flanked with loxP sites. UTX has been found to be a tumor 
suppressor gene mutated in a wide variety of human cancers. The UTX-
flox mice provide a valuable tool to study how

[[Page 24505]]

UTX functions as a tumor suppressor and as an epigenetic regulator of 
gene expression.
    Potential Commercial Application: Mouse model for Oncology 
research.
    Development Stage: Pre-clinical.
    Developer of Mouse: Kai Ge, Ph.D. (NIDDK).
    Relevant Publication: Unpublished. Gene ID: 22289.
    Intellectual Property: HHS Reference No. E-118-2012/0--Research 
Tool. Patent protection is not being pursued for this technology.
    Licensing Contact: Mojdeh Bahar, J.D., CLP; 301-435-2950; 
baharm@mail.nih.gov.

    Dated: April 18, 2012.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 2012-9775 Filed 4-23-12; 8:45 am]
BILLING CODE 4140-01-P