Project #1: Microassisted Fertilization and Genetic Defects - This proposal seeks continued support to determine the molecular basis of non-obstructive azoospermia (no sperm in the ejaculate) in the human. During our current funding period we tested the hypothesis that genomic instability is associated with azoospermia or severe oligospermia (few sperm in the ejaculate). We defined defects in DNA mismatch repair in men with Sertoli cell only syndrome (no spermatogenic cells in the testis, except for occasional rare foci). Loss of MLH1 or MSH2 mismatch repair gene expression in the Sertoli cell only fathers results in a mutator phenotype"""""""" with a greatly diminished fidelity of the genome. Absent or abnormal expression of the mismatch repair proteins, MLH1 and MSH2 in Sertoli cell only patients was associated with a high level of microstatellite or genomic instability and a high rate of mutation. Microsatellite instability was associated with expansion of repetitive sequences of DNA associated with neurodegenerative diseases in the testis/sperm and the somatic tissues of Sertoli cell only men. A 64-fold increase in the incidence of a triplet repeat neurodegenerative disease, Myotonic dystrophy, was observed in men with non-obstructive azoospermia compared to the normal population. Because of the intrinsic defect in DNA repair present in the Sertoli cell only father, children conceived by injection of rare sperm (obtained by testicular sperm extraction used in combination with Intracytoplasmic sperm injection [TESE-ICSI]) may be at high risk of developing adult onset neurodegenerative diseases or other gene mutations. The proposed studies focus on the safety of TESE-ICSI for these children and examine whether they exhibit disease range nucleotide repeat expansions. The molecular basis for this instability will be determined (mutation or epimutation in MSH2 and MLH1). We hypothesize that the genomic instability seen differs from that seen in the triplet repeat diseases. We will characterize the paternal transmission by TESE-ICSI of neurodegenerative disease loci alleles. Finally, we will expand our analysis to test the hypothesis that defects in MSH3, 4, and 5 (genes involved in synapsis and crossing over in meiosis, rather than mismatch repair) are associated an increased level of chromosome nondisjunction causing a meiotic arrest and non-obstructive azoospermia. The long term goal of this study is to define the molecular causes of non-obstructive azoospermia and the safety for the offspring when TESE-ICSI is used to achieve an otherwise impossible pregnancy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD036289-10
Application #
8102878
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
2012-09-30
Budget Start
2010-04-01
Budget End
2012-09-30
Support Year
10
Fiscal Year
2010
Total Cost
$247,051
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Carrell, D T; Nyboe Andersen, A; Lamb, D J (2015) The need to improve patient care through discriminate use of intracytoplasmic sperm injection (ICSI) and improved understanding of spermatozoa, oocyte and embryo biology. Andrology 3:143-6
Garcia, Jose M; Chen, Ji-an; Guillory, Bobby et al. (2015) Ghrelin Prevents Cisplatin-Induced Testicular Damage by Facilitating Repair of DNA Double Strand Breaks Through Activation of p53 in Mice. Biol Reprod 93:24
Gomez, Lissette; Kovac, Jason R; Lamb, Dolores J (2015) CYP17A1 inhibitors in castration-resistant prostate cancer. Steroids 95:80-7
Eisenberg, Michael L; Li, Shufeng; Betts, Paul et al. (2015) Testosterone therapy and cancer risk. BJU Int 115:317-21
Jorgez, Carolina J; Wilken, Nathan; Addai, Josephine B et al. (2015) Genomic and genetic variation in E2F transcription factor-1 in men with nonobstructive azoospermia. Fertil Steril 103:44-52.e1
Eisenberg, M L; Li, S; Herder, D et al. (2015) Testosterone therapy and mortality risk. Int J Impot Res 27:46-8
Eisenberg, Michael L; Li, Shufeng; Behr, Barry et al. (2014) Semen quality, infertility and mortality in the USA. Hum Reprod 29:1567-74
Kovac, Jason R; Rajanahally, Saneal; Smith, Ryan P et al. (2014) Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. J Sex Med 11:553-62
Kovac, Jason R; Pan, Michael M; Lipshultz, Larry I et al. (2014) Current state of practice regarding testosterone supplementation therapy in men with prostate cancer. Steroids 89:27-32
Kovac, Jason R; Kovac, Jason; Pastuszak, Alexander W et al. (2014) Testosterone supplementation therapy in the treatment of patients with metabolic syndrome. Postgrad Med 126:149-56

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