Decreased peak bone density, increased embryonic aneuploidy, and decreased fertility are each clinical examples of the onset of a perimenopausal transition which begins in the mid-thirties. This project is directed at understanding the biological basis of this transition by investigating granulosa cells which are fundamental components of the aging follicle. The overall goal of this project is to investigate age-dependent changes in the human granulosa cell. The working hypothesis is that reproductive aging results in an ovarian follicle containing somatic cells (granulosa cells) and germ cells (oocytes) which are of compromised quality (diminished ovarian reserve) as compared to their respective components in younger women. As healthy granulosa are essential for oocyte viability this proposal focuses upon cellular and genetic aspects of granulosa cells within the follicle. The study will explore how age-dependent alterations in the granulosa cell cycle can lead to default pathways resulting in increased granulosa cell apoptosis. An investigation into whether the differential expression of the Bcl-2 gene family and/or an increase in mitochondrial mutations are associated with an increased rate of granulosa cell apoptosis found in women with diminished ovarian reserve will be made. Finally, the mitochondrial mechanisms by which granulosa cell apoptosis occurs as a function of diminished ovarian reserve will be explored.
The specific aims are: 1) to evaluate the age-related differences in cell cycle kinetics of granulosa cells and to determine if these changes are associated with different rates of apoptosis in granulosa cells, 2) to examine age-related differences in mitochondrial DNA mutations, nuclear-coded mitochondrial genes and Bcl-2 gene family expression as a function of diminished ovarian reserve, 3) to investigate the mitochondrial mechanisms by which granulosa apoptosis occurs as a function of diminished ovarian reserve.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AG015425-06
Application #
6533788
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Bellino, Francis
Project Start
1998-05-01
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
6
Fiscal Year
2002
Total Cost
$111,300
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Feng, Bo; Chen, Shiling; Shelden, Robert M et al. (2003) Effect of gonadotropins on brain-derived neurotrophic factor secretion by human follicular cumulus cells. Fertil Steril 80:658-9
Seifer, David B; Lambert-Messerlian, Geralyn; Schneyer, Alan L (2003) Ovarian brain-derived neurotrophic factor is present in follicular fluid from normally cycling women. Fertil Steril 79:451-2
Hock, Doreen L; Seifer, David B; Kontopoulos, Eftichia et al. (2002) Practice patterns among board-certified reproductive endocrinologists regarding high-order multiple gestations: a united states national survey. Obstet Gynecol 99:763-70
Chin, Khew-Voon; Seifer, David B; Feng, Bo et al. (2002) DNA microarray analysis of the expression profiles of luteinized granulosa cells as a function of ovarian reserve. Fertil Steril 77:1214-8
Seifer, David B; Feng, Bo; Shelden, Robert M et al. (2002) Neurotrophin-4/5 and neurotrophin-3 are present within the human ovarian follicle but appear to have different paracrine/autocrine functions. J Clin Endocrinol Metab 87:4569-71
Seifer, David B; DeJesus, Vimaris; Hubbard, Karen (2002) Mitochondrial deletions in luteinized granulosa cells as a function of age in women undergoing in vitro fertilization. Fertil Steril 78:1046-8
Seifer, David B; Feng, Bo; Shelden, Robert M et al. (2002) Brain-derived neurotrophic factor: a novel human ovarian follicular protein. J Clin Endocrinol Metab 87:655-9
Trout, S W; Seifer, D B (2000) Do women with unexplained recurrent pregnancy loss have higher day 3 serum FSH and estradiol values? Fertil Steril 74:335-7
Dzik, A; Lambert-Messerlian, G; Izzo, V M et al. (2000) Inhibin B response to EFORT is associated with the outcome of oocyte retrieval in the subsequent in vitro fertilization cycle. Fertil Steril 74:1114-7
Houmard, B S; Seifer, D B (1999) Infertility treatment and informed consent: current practices of reproductive endocrinologists. Obstet Gynecol 93:252-7

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