Fertilin is a member of the ADAM super family of extracellular matrix proteins containing disintegrin and metalloprotease domains that are known to function in fertilization, myoblast fusion, neurogenesis, and shedding of receptor ectodomains. Fertilin is present on the extracellular surface of sperm, and binds to the alpha6beta1 integrin on the egg. The goal of these studies is to explore the role of other ADAM proteins present on the sperm surface, as well as to investigate the fertilinbeta- alpha6beta1 integrin ligand-receptor pair. Specific questions that will be addressed are: 1) What are the functions of other ADAM proteins on the sperm surface, and do they have their own adhesion partners? Photoaffinity labeling experiments will be used to address this question. 2) What is the required density of sperm ADAM ligands for maximal inhibition of sperm-egg adhesion? Polyvalent molecules and membrane mimics will be synthesized and tested as inhibitors of in vitro fertilization. 3) Does binding of sperm ADAMs to egg integrins cause egg activation? The polyvalent probes prepared in aim number 2 will be tested to see if they initiate cortical granule exocytosis, Ca2+ oscillations or second polar body formation. 4) What controls the function of alpha6beta1 integrin? The binding affinity and avidity of fertilinbeta for alpha6beta1 on the egg will be determined as a function of three stimuli: divalent cations, activating beta1 antibody, and an EGF-like peptide from fertilinbeta. These studies will investigate what regulates the binding of alpha6beta1 to its two known ligands, fertilinbeta and laminin. The significance of the work proposed is 2-fold. (i) To understand at the molecular level the affinities and specificities of ADAM proteins for their receptors and hence their function. (ii) To elucidate what initiates signaling pathways in fertilization and egg activation. These results will give insight into the functions of ADAM disintegrins in many physiological processes such as myoblast fusion and neurogenesis, in addition to fertilization. In addition, they will contribute to understanding the reasons for infertility and to the development of new approaches to contraception.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038519-02
Application #
6363454
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Tasca, Richard J
Project Start
2000-03-01
Project End
2004-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$242,566
Indirect Cost
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Lee, Siyeon; Wang, Wei; Lee, Younjoo et al. (2015) Cyclic acetals as cleavable linkers for affinity capture. Org Biomol Chem 13:8445-52
Wu, Linghui; Sampson, Nicole S (2014) Fucose, mannose, and ?-N-acetylglucosamine glycopolymers initiate the mouse sperm acrosome reaction through convergent signaling pathways. ACS Chem Biol 9:468-75
Romulus, Joy; Tan, Li; Weck, Marcus et al. (2013) Alternating ROMP copolymers containing charge-transfer units. ACS Macro Lett 2:749-752
Song, Airong; Walker, Stephen G; Parker, Kathlyn A et al. (2011) Antibacterial studies of cationic polymers with alternating, random, and uniform backbones. ACS Chem Biol 6:590-9
Song, Airong; Parker, Kathlyn A; Sampson, Nicole S (2010) Cyclic alternating ring-opening metathesis polymerization (CAROMP). Rapid access to functionalized cyclic polymers. Org Lett 12:3729-31
Song, Airong; Lee, Jae Chul; Parker, Kathlyn A et al. (2010) Scope of the ring-opening metathesis polymerization (ROMP) reaction of 1-substituted cyclobutenes. J Am Chem Soc 132:10513-20
Baessler, Keith A; Lee, Younjoo; Sampson, Nicole S (2009) Beta1 integrin is an adhesion protein for sperm binding to eggs. ACS Chem Biol 4:357-66
Lee, Younjoo; Sampson, Nicole S (2009) Polymeric ADAM protein mimics interrogate mammalian sperm-egg binding. Chembiochem 10:929-37
Song, Airong; Parker, Kathlyn A; Sampson, Nicole S (2009) Synthesis of copolymers by alternating ROMP (AROMP). J Am Chem Soc 131:3444-5

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