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INVESTIGATION OF XRCC5 MUTANT MICE

Award Number: R01CA076317
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/1997
PERIOD OF PERFORMANCE END DATE: 03/31/2006

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INVESTIGATION OF XRCC5 MUTANT MICE - Genomic instability is a major cause of cancer and believed to be a major contributor to aging. The gene Xrcc5, that codes for the protein, Ku80 is important for maintaining genomic stability by repairing double-strand breaks (DSBs) in DNA and by capping chromosomal ends. Mice deleted for Ku80 are immunodeficient due to defective repair of DSBs that occur during Variable (Diversity) Joining recombination and cells derived from ku80-mutant mice are hypersensitive to ionizing radiation and reactive oxygen species. In addition, these cells exhibit cytogenetic aberrations including telomeric fusions. ku80-mutant mice exhibit an early onset of age-related changes in a variety of tissues that are also observed in control mice; thus, Ku80 may be important for the normal aging process. These changes include growth plate closure, osteopenia, skin and follicular atrophy, degenerative processes in the liver and shortened life span. Early mortality was at least partly due to early onset of the age - specific diseases, sepsis and cancer. Even though onset of cancer is early for ku80-mutant mice, the total incidence is low. Interestingly, deletion of the tumor suppressor protein, p53, greatly increased the risk of lymphoma suggesting that Ku80 is also a tumor suppressor. The biological role of Ku80 in maintaining genomic stability will be determined during aging and oncogenesis and completion of this proposal will significantly impact our understanding of Ku80's role during these events. l: Determine the contribution genomic instability, induced by either oxidative damage or telomere dysfunction, has on the ku80-mutant phenotype. The onset and spectra of genetic mutations will be compared between ku80-mutant and control mice. To determine the impact of oxidative damage, DNA lesions will be measured in ku80- mutant mice after exposure to ionizing radiation and by overexpressing proteins that eliminate oxygen radicals, catalase and Cu/Zn-superoxide dismutase. To investigate the impact of telomere maintenance, ku80-/- mTR-/- mice will be investigated. 2: Determine the impact general genomic instability has on oncogenesis in ku80-mutant mice that are deleted for p53 in nonlymphoid tissue. The role of the tumor suppression protein, p53, will be analyzed for its impact on oncogenesis in ku80-mutant mice with specific attention given to mammary tissue in a defined mouse model.


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: 2005 ( Subtotal = $259,880 )
2005	2005	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Cancer Cause and Prevention Research	000	8	3/4/2005	NON-COMPETING CONTINUATION	$259,880
														Subtotal = $259,880

Issue Date FY: 2004 ( Subtotal = $259,880 )
2004	2004	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Cancer Cause and Prevention Research	000	7	2/13/2004	NON-COMPETING CONTINUATION	$259,880
														Subtotal = $259,880

Issue Date FY: 2003 ( Subtotal = $259,880 )
2003	2003	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Cancer Cause and Prevention Research	000	6		NON-COMPETING CONTINUATION	$259,880
														Subtotal = $259,880

Issue Date FY: 2002 ( Subtotal = $259,509 )
2002	2002	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Cancer Cause and Prevention Research	000	5	2/26/2002	COMPETING CONTINUATION	$259,509
														Subtotal = $259,509

Issue Date FY: 1999 ( Subtotal = $195,727 )
1999	1999	LEXICON GENETICS	4000 RESEARCH FOREST DRIVE	THE WOODLANDS	TX	77381	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	3	5/10/1999	NON-COMPETING CONTINUATION	$195,727
														Subtotal = $195,727

Issue Date FY: 1998 ( Subtotal = $190,024 )
1998	1998	LEXICON GENETICS	4000 RESEARCH FOREST DRIVE	THE WOODLANDS	TX	77381	MONTGOMERY	USA	Cancer Cause and Prevention Research	000	2	5/26/1998	NON-COMPETING CONTINUATION	$190,024
														Subtotal = $190,024

Grand Total All Awards = $1,424,900

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INVESTIGATION OF XRCC5 MUTANT MICE

Award Number: R01CA076317

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/07/1997

PERIOD OF PERFORMANCE END DATE: 03/31/2006

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