A variety of disorders, including autism, schizophrenia, achondroplasia, Apert Syndrome, and some cancers are more common in those born to older fathers. This association has been referred to as the paternal age effect (PAE). High-throughput, low-cost DNA sequencing techniques have recently yielded very large numbers of candidate de novo alleles in some of these diseases (e.g., autism and schizophrenia). Positive selection of mutant spermatogonial stem cells (SSCs) in the human testis may enable aberrant sperm to contribute such de novo mutant alleles to the next generation, resulting in the observed pathology. We are addressing this hypothesis by manipulating adult SSCs in culture, in conjunction with transplantation in vivo, in order to provide direct, experimental evidence for a putative mechanism of PAEs. The goals of the project are to address the mechanisms of specific disease-associated mutations and develop a protocol to discover and rapidly validate novel mutations. In order to design strategies to prevent or treat inherited disorders, an understanding of their molecular origins will be extremely valuable. The experiments described herein would support a common mechanism for PAEs and would show that PAE diseases could be considered prototypical stem cell-based diseases. An in vitro modeling approach to mutant allele discovery could eventually overcome some of the technical barriers to identification of genetic lesions associated with multigenic PAE diseases (e.g., autism), which otherwise requires large human data sets. By improving our understanding of the cellular basis for PAE disease pathogenesis and the roles of discrete mutations, experimental manipulation of SSCs could lead directly to novel therapeutic strategies for patients.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2HD080352-01
Application #
8570427
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (56))
Program Officer
Moss, Stuart B
Project Start
2013-09-19
Project End
2018-08-31
Budget Start
2013-09-19
Budget End
2018-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$2,527,500
Indirect Cost
$1,027,500
Name
Weill Medical College of Cornell University
Department
Surgery
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Sachs, C; Robinson, B D; Andres Martin, L et al. (2014) Evaluation of candidate spermatogonial markers ID4 and GPR125 in testes of adult human cadaveric organ donors. Andrology 2:607-14
Martin, Laura A; Assif, Nicholas; Gilbert, Moses et al. (2014) Enhanced fitness of adult spermatogonial stem cells bearing a paternal age-associated FGFR2 mutation. Stem Cell Reports 3:219-26