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IDENTIFICATION OF COLON CANCER GENES VIA RETROTRANSPOSON MUTAGENESIS

Award Number: F32CA126294
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2006
PERIOD OF PERFORMANCE END DATE: 09/29/2009

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IDENTIFICATION OF COLON CANCER GENES VIA RETROTRANSPOSON MUTAGENESIS - DESCRIPTION (provided by applicant): Mutations caused by DNA damage in the cell is a major cause of cancer. Familial mutations in colorectal cancer (CRC) account for less than 3% of all CRC cases, while other key tumor suppressors or proto-oncogenes remain unidentified. For sporadic CRC, pinpointing the causative mutation(s) within a cancer containing many mutations and epigenetic modifications is also incredibly difficult. Thus, it is likely that many genetic modifiers and causative mutations remain unidentified. Recent developments of mutagenesis strategies in the mouse now make it possible to rapidly identify causative mutations and modifiers involved in carcinogenesis. The objectives of this proposal are (1) to develop a transgenic mouse model of colorectal cancer through random insertional mutagenesis in the intestinal epithelium, and (2) to identify novel cancer modifier genes within a mouse model of CRC. Genes to be identified include novel cancer genes and pathways, modifiers of APC/Wnt signaling, and synergistic or cooperative mutations. This proposal details a novel forward genetics approach using a transgenic L1 retrotransposon mutagenesis system. Two mutagenic L1 cassettes will be used in this proposal: one containing a small bidirectional splice acceptor gene trap for interruption of gene expression (LOF module), and one containing a constitutive promoter and splice donor for over-expression of possible oncogenes (GOF module). Both transgene cassettes will employ the mouse Vil1 (Villin) promoter. This promoter is unique in its ability to drive specific high-level copy-number dependent expression throughout the entire intestinal epithelium: in stem cells, progenitors, and differentiated cells. Polyps from a transgenic mouse can be harvested and mutations readily identified by ligation-mediated PCR of genomic DNA or by 3' RACE of RNA. Relevance: This proposal describes a method employing powerful genetic tools developed in the mouse for specifically targeting the intestinal epithelium, the tissue where colorectal cancer originates. This approach can potentially identify hundreds of cancer gene mutations in a single mouse, as opposed to traditional methods where only one gene is mutated in a single mouse. Thus, one can rapidly identify many mutations that have the ability to cause colorectal cancer. This may uncover new mechanisms for how cancer initiates.


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 = $0 )
2009	2008	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	001	5	7/24/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$19,505
2009	2008	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3701 Market St FL 4	Philadelphia	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	4	7/21/2009	NON-COMPETING CONTINUATION	-$19,505
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $50,428 )
2008	2008	TRANSPOSAGEN BIOPHARMACEUTICALS INC	3160 CHESTNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	4	9/10/2008	NON-COMPETING CONTINUATION	$50,428
														Subtotal = $50,428

Issue Date FY: 2007 ( Subtotal = $48,796 )
2007	2007	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	2	8/20/2007	NON-COMPETING CONTINUATION	$48,796
														Subtotal = $48,796

Issue Date FY: 2006 ( Subtotal = $45,976 )
2006	2006	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	9/21/2006	NEW	$45,976
														Subtotal = $45,976

Grand Total All Awards = $145,200

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IDENTIFICATION OF COLON CANCER GENES VIA RETROTRANSPOSON MUTAGENESIS

Award Number: F32CA126294

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2006

PERIOD OF PERFORMANCE END DATE: 09/29/2009

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