Directory > Faculty
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Associate Professor
Animal Biotechnology
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4173 Biomedical and Physical Sciences
Dept. of Physiology
Michigan State University
East Lansing, MI 48824-1225
Phone: (517) 355-6475 ext 1158
Fax: (517) 355-5125
E-mail: perezg@msu.edu
Areas
of Research Interest
Education
D.V.M., University of Antioquia, Colombia
Ph.D., University of Wisconsin-Madison
Accumulation of unrepaired DNA damage in ovaries of aging women
or those undergoing chemotherapy results in genomic instability
with consequential triggering of massive germ cell loss through
apoptosis. In essence ovarian failure ensues, characterized by
loss of fertility and/or propulsion into menopause. With the current
levels of life expectancy, women are predicted to spend a third
of their lifetime combating age-related health complications associated
with ovarian failure at the onset of menopause. A partial solution
to this predicament is possible through genetic manipulation as
exemplified by disrupting the bax gene to produce knock-out mice
bearing a surfeit of primordial follicles that extends ovarian
lifespan well into advanced chronological age, and their oocytes
resistant to chemotherapy-induced apoptosis. Further progress
in this research area is limited though, and several questions
remain unanswered. Therefore, the focus of my research is to fill
this gap, and is driven by three specific aims: (1) Determine
the mechanism(s) of resistance to death in oocytes; such mechanism
is inherent in bax knockout-mice; (2) Identify the earliest key
regulatory molecules activated/deactivated and subsequent event(s)
leading to oocyte death; (3) Determine the impact of enhancing
DNA repair molecules on oocyte endowment.
Our main research projects include:
1. Oocyte Genomic Instability in Aging and Chemotherapy
The objective of this project is to identify and describe the
interaction between Bax and Rad51, a protein involved in cell
viability and in DNA repair, and how this determines survival
of female germ cells during aging and after doxorubicin treatment.
2. Ceramide Modulation of Death in Germ Cells of Aging Females
The objective of this project is to determine the molecular basis
for sphingolipid (e.g., ceramide) modulated increased germ cell
loss with age. The research design will use mice as a model to
study distribution and turnover of ceramide, and how these relate
to oocyte apoptosis.
3. Role of Sphingolipids in Doxorubicin Trafficking
This project is directed at elucidating the details of sphingolipid
(e.g., ceramide) and doxorubicin movement in cells undergoing
apoptosis. Targeting ceramide metabolic and cell death signaling
pathways is a potential clinical treatment strategy for overcoming
drug resistance.
4. A Novel Role for Cell Death in Fertilization
While homing through the cumulus cell (CC) mass, the spermatozoa
seem to induce a coupled cell death-survival mechanism that is
programmed genetically to favor the survival of the maturing oocyte
while simultaneously promoting death of CC. Hence, this project
expects to answer the following questions: How do sperm control
CC induced-oocyte maturation while ensuring their arrival at the
target on time? Is it necessary to kill the CC? And, what is the
mechanism responsible for the killing?
Publications (last five years)
Robles R, Morita Y, Mann KK, Perez GI, Yang S, Matikainen T, Sherr
DH, Tilly JL. The Aryl hydrocarbon receptor, a basic helix-loop-helix
transcription factor of the PAS gene family, is required for normal
ovarian germ cell dynamics in the mouse. Endocrinology 2000; 141:450-453.
Perez GI, Trbovich AM, Gosden RG, Tilly JL. Mitochondria and
the death of oocytes. Nature 2000, 403:500-501.
Perez GI, Hughes FM, Maravei DV, Trbovich AM, Cidlowiski JA,
Tilly JL. A role for potassium in regulating caspase and nuclease
activities during apoptosis in ovarian germ cells and granulosa
cells. Biology of Reproduction 2000, 63:1358-1369.
Morita Y, Perez GI, Miranda SR, Ehleiter D, Paris F, Xie Z, Reed
JC, Haimovitz Friedman A, Fuks Z, Schuchman EH, Kolesnick RN,
Tilly JL. The sphingomyelin pathway governs female germ cell fate.
Nature Medicine 2000, 6:1100-1109. (*equal contributors, co-first
authors. Article listed on cover).
Matikainen T, Perez GI, Zheng TS, Flavell RA, Kluzak TR, Rueda
BR, Tilly JL. Caspase-3 gene knockout defines cell lineage specificity
for programmed cell death signaling in the ovary. Endocrinology
2001, 142:2468-2480.
Matikainen T, Perez GI, Jurisicova A, Schlezinger JJ, Ryu HY,
Laine J, Sakai T, Korsmeyer, SJ, Casper RF, Sherr DH, Tilly JL.
Aromatic hydrocarbon receptor-driven bax gene expression is required
for premature ovarian failure cuased by biohazardous environmental
chemicals. Nature Genetics 2001, 28:355-360.
Paris F, Perez GI, Morita Y, Tilly JL, Fuks Z, Kolesnick RN.
Comment bloquer l´apoptose des ovocytes? Medecine Sciences 2001,
17:230-231.
Morita Y, Maravei DV, Bergeron L, Wang S, Perez GI, Tsutsumi
O, Taketani Y, Asano M, Horai R, Korsmeyer SJ, Iwakura Y, Yuan
J, Tilly JL. Caspase-2 deficiency rescues female germ cells from
death due to cytokine insufficiency but not meiotic defects caused
by ataxia telangiectasia-mutated (Atm) gene inactivation. Cell
Death & Differentiation 2001; 8:614-620.
Ren D, Navarro B, Perez GI, Jackson AC, Hsu S, Shi Q, Tilly JL,
Clapham DE. A sperm ion channel required for sperm motility and
male fertility. Nature 2001; 413:603-609. (highlighted by an accompanying
News & Views commentary).
Matikainen TM, Moriyama T, Morita Y, Perez GI, Korsmeyer SJ,
Sherr DH, Tilly JL. Ligand activation of the aromatic hydrocarbon
receptor transcription factor drives Bax-dependent apoptosis in
developing fetal ovarian germ cells. Endocrinology 2002, 143:615-620.
Paris F, Perez GI, Haimovitz-Friedman A, Nguyen Hai, Bose M,
Ilagan A, Hunt PA, Morgan WF, Tilly JL, Kolesnick R. Sphingosine
1-phosphate preserves fertility in irradiated female mice without
propagating genomic damage in offspring. Nature Medicine 2002;
8:901-902 (*equal contributors, co-first authors).
Takai Y, Canning J, Perez GI, Pru J, Schlezinger J, Sherr DH,
Kolesnick RN, Yuan J, Flavell RA, Kosmeyer SJ, Tilly JL. Bax,
Caspase-2 and Caspase-3 are required for ovarian follicle loss
caused by 4-vinylcyclohexene diepoxide exposure in vivo. Endocrinology
2003, 144:69-74.
Otala M, Pentikainen MO, Matikainen T, Suomalainen L, Hakala
JK, Perez GI, Tenhunen M, Erkkila K, Kovanen P, Parvinen M, Dunkel
L. Effects of acid sphingomyelinase deficiency on male germ cell
development and programmed cell death. Biology of Reproduction
2005; 72:86-96.
Perez GI*, Jurisicova A, Matikainen T, Moriyama T, Takai Y, Pru
JK, Kolesnick RN, Tilly JL. A central role for ceramide in the
age-related acceleration of apoptosis in the female germ line.
FASEB J. 2005; Feb 23; [Epub ahead of print]. (*corresponding
author).
Jurisicova A, Lee HJ, D´Estaing SG, Tilly JL, Perez GI*. Molecular
requirements for doxorubicin death in murine oocytes. Cell Death
and Differentiation 2006; In Press. (*corresponding author).
Other Publications
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