Chromatin integrity has been identified as an important prerequisite for normal sperm cell function. Incomplete chromatin condensation and the presence of persistent DMA strand breaks indicate a severe reduction of the fertilization potential in mature spermatozoa. These deficiencies can often result from faulty or incomplete execution of chromatin remodeling steps and DMA strand break management in immature steps of spermatid development. The objective of the proposed project is to identify basic functions of ADP-ribose (ADPR) polymer metabolism in germ cell differentiation that can be targeted for pharmacological intervention to prevent the persistence of residual DNA damage in germinal cells, particularly, but not limited to, men who have circumstantially been exposed to DNA damaging agents. The objective of the proposed project is to identify mechanisms of PARP-1, PARC and poly (ADP-ribose) function in postmeiotic germ cell maturation and to define the impact of ADP-ribose metabolism on the genetic and structural integrity of sperm cells. Based on our preliminary data, the central hypothesis for the proposed research is that ADPR polymer metabolism is required for efficient DNA strand break mediated chromatin reorganization during spermatid maturation.
3 specific aims are proposed: 1.) Determine parameters of mature sperm cell quality affected by ADPR polymer metabolism. 2.) Define the extent to which ADP-ribose polymer metabolism contributes to the repair of DNA strand breaks in spermatid nuclei. 3.) Identify target proteins of poly(ADP-ribosyl)ation in spermatid cells. The proposed investigations are expected to provide novel insights into the function of ADPR polymer metabolism in the maintenance of sperm cell quality. The project is innovative in its utilization of an interdisciplinary approach and the unique animal models that are involved. This research is significant because it is expected to contribute to the development of new therapeutic approaches that target ADPR polymer metabolism for the treatment of male fertility problems.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD048837-01A1
Application #
6968076
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Rankin, Tracy L
Project Start
2005-08-10
Project End
2010-05-31
Budget Start
2005-08-10
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$303,131
Indirect Cost
Name
University of Pennsylvania
Department
Neurosciences
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Meyer-Ficca, Mirella L; Lonchar, Julia D; Ihara, Motomasa et al. (2013) Alteration of poly(ADP-ribose) metabolism affects murine sperm nuclear architecture by impairing pericentric heterochromatin condensation. Chromosoma 122:319-35
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Bermudez, Yira; Benavente, Claudia A; Meyer, Ralph G et al. (2011) Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation. PLoS One 6:e20487
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Meyer, Ralph G; Meyer-Ficca, Mirella L; Whatcott, Clifford J et al. (2007) Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity. Exp Cell Res 313:2920-36