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L1 RETROTRANSPOSON-BASED MUTAGENESIS FOR RAT MODELS OF HUMAN DISEASES

Award Number: R44RR021289
ORGANIZATION: NATIONAL CENTER FOR RESEARCH RESOURCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/14/2005
PERIOD OF PERFORMANCE END DATE: 05/31/2010

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L1 RETROTRANSPOSON-BASED MUTAGENESIS FOR RAT MODELS OF HUMAN DISEASES - DESCRIPTION (provided by applicant): In many aspects the rat is a better animal model than the mouse for functional genomic studies. The physiology and drug metabolism of rats and humans are more similar than that of mice and humans. The rat is larger than the mouse, making many studies easier to perform and sampling more accurate. The recent completion of the Brown Norway rat genome improves further the potential of the rat as an excellent organism for studying human diseases. Unfortunately, many genetic manipulation techniques available in the mouse such as random mutagenesis with a gene trap (both retroviral-based and non-retroviral-based), gene knock- outs, gene knock-ins, and conditional mutations have not been possible in the rat because there is no way to effectively harvest and culture rat embryonic stem cells. Existing methods for producing gene deletions in rats, including cloning and chemical mutation, are inefficient and not practical. This deficiency leads to a severe bottleneck in our ability to create rat models of human disease. The product that will arise from this proposal will be rats with single gene knockouts for use as models of human disease in research and drug discovery (MutaRat Animal Models). Transposagen has developed a novel technology, based on human L1 retrotransposons, to generate animals with a high rate of random gene mutations in germ cells.In MutaRats, mutagenesis will occur in sperm and oocytes and some offspring will contain single gene disruptions. These offspring can be used to establish authentic gene knockout rat lines. In Phase I we successfully developed and characterized MutaMice, generating 22 potential founders.We have subsequently developed similar "mutator" founder rats (MutaRats), and in Phase II, we intend to characterize these rats, and use them to generate rats with stable, singe gene deletions (gene knockout MutaRat Animal Models). Specific aim 1 isto screen existing MutaRatfounder lines to determine the line with the highest frequency of mutation. This line will then be bred to establish a breeding colony that can be used to obtain single gene knockout rats in Specific Aim 2. We do not intend to characterize the phenotypes of these lines, nor to establish breeding colonies of individual knockout rat linesas part of this proposal, but instead to establish a sperm bank comprising sequenced insertional gene disruptions, the MutaRat Germ Line Resource. In Specific Aim 3 we will develop the MutaRat Germ Line Resourceof cryopreserved sperm from rats with single gene knockouts. We estimate that we will have a sperm bank with at least 100 different gene knockouts by the endof this project in December, 2008. This MutaRat Germ Line Resource will be the only technology capable of creating and rapidly mapping random gene knockouts in rats. Knockout ratswill be provided to the academic community in accordance with the NIH policy on sharing of model organisms for biomedical research and will be distributed by the National Rat Resource and Research Center. In Phase III, we will establish a distribution partnership with an existing laboratory animal company to market, establish and validate (as necessary), and distribute these lines, and others as they are developed. The innovation of this proposal is the use of a novel retrotransposon technology to create the only system able to rapidly create and map insertional deletions in the rat and other mammals. This technology is expected to offer significant advantages in cost and speed when compared with existing mutagenesis systems available in mice, and to generate novel gene knockout models that have not previously been available in any vertebrate. Transposagen's MutaRat Animal Models will contribute to human health by providing new vertebrate models of disease for studying pathogenesis and for discovery and development of pharmaceutical compounds.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2009 ( Subtotal = $227,342 )
2009	2009	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3701 Market St FL 4	Philadelphia	PA	19104	PHILADELPHIA	USA	National Center for Research Resources	003	3	1/12/2009	SUPPLEMENT FOR EXPANSION	$189,865
2009	2008	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3160 CHESTNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center for Research Resources	002	3	12/15/2008	NON-COMPETING CONTINUATION	$0
2009	2008	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3160 CHESTNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center for Research Resources	001	3	11/3/2008	NON-COMPETING CONTINUATION	$0
2009	2007	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3701 Market St FL 4	Philadelphia	PA	19104	PHILADELPHIA	USA	National Center for Research Resources	000	2	12/10/2008	COMPETING CONTINUATION	$37,477
														Subtotal = $227,342

Issue Date FY: 2008 ( Subtotal = $668,320 )
2008	2008	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3160 CHESTNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center for Research Resources	000	3	9/12/2008	NON-COMPETING CONTINUATION	$668,320
														Subtotal = $668,320

Issue Date FY: 2007 ( Subtotal = $650,666 )
2007	2007	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3160 CHESTNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center for Research Resources	000	2	5/22/2007	COMPETING CONTINUATION	$650,666
														Subtotal = $650,666

Grand Total All Awards = $1,546,328

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L1 RETROTRANSPOSON-BASED MUTAGENESIS FOR RAT MODELS OF HUMAN DISEASES

Award Number: R44RR021289

ORGANIZATION: NATIONAL CENTER FOR RESEARCH RESOURCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/14/2005

PERIOD OF PERFORMANCE END DATE: 05/31/2010

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