This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cell-cell junctions are important in physiological processes, with tight junctions helping to maintain the epithelial cell layer that protects multicellular organisms from the environment. Cell surface adhesion proteins involved in forming these junctions play a role in the loss of attachment, which leads cells to become migratory. We have identified and characterized a novel cell adhesion molecule, Junctional Adhesion Molecule-A (JAM-A), which is expressed at endothelial and epithelial cell tight junctions. Our results implicate JAM-A in the events leading to migratory behavior, including cancer cell metastasis, as well as in subfertility. We therefore propose to test the following hypotheses in this proposal: 1) Metastatic behavior of breast cancer cells is related to the expression level of JAM-A. We will determine the expression of JAM-A in breast cancer cell lines with a range of metastatic potentials. We will compare the expression of JAM-A to the metastatic potential, and use cellular and mouse models to confirm the relationship. 2) Post-translational modifications of JAM-A influence the metastatic ability of breast cancer cells. We will determine if post-translational modification of JAM-A is related to the metastatic behavior of these cells. Again we will utilize in vitro, as well as in vivo, models of tumor metastasis. 3) Signaling through JAM-A regulates the metastatic potential of breast cancer cells. The intracellular signaling pathway induced through JAM-A will be characterized. 4) Reduced expression and/or post-translational modification of JAM-A affect spermiogenesis leading to sperm lacking the protein on the heads and the flagellum. Consequently, there is reduced motility and disruption of the signal transduction and protein phosphorylation properties. We will determine the effect of the absence of JAM-A on basal intracellular calcium in both capacitated and uncapacitated sperm to determine its role in calcium signaling which is involved in both progressive and hyperactivated motility. We will also determine if JAM-A is present in a multi-protein signaling complex with Plasma membrane calcium ATPase4 (PMCA4) and Calcium serine kinase (CASK) which are flagellar signaling molecules. Our results will help define the role of JAM-A in cancer cell metastasis and male subfertility resulting from reduced sperm motility, and can identify therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015588-10
Application #
7959539
Study Section
Special Emphasis Panel (ZRR1-RI-8 (01))
Project Start
2009-06-01
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$410,843
Indirect Cost
Name
University of Delaware
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Li, Linqing; Stiadle, Jeanna M; Levendoski, Elizabeth E et al. (2018) Biocompatibility of injectable resilin-based hydrogels. J Biomed Mater Res A 106:2229-2242
Bathala, Pradeepthi; Fereshteh, Zeinab; Li, Kun et al. (2018) Oviductal extracellular vesicles (oviductosomes, OVS) are conserved in humans: murine OVS play a pivotal role in sperm capacitation and fertility. Mol Hum Reprod 24:143-157
Olli, Kristine E; Li, Kun; Galileo, Deni S et al. (2018) Plasma membrane calcium ATPase 4 (PMCA4) co-ordinates calcium and nitric oxide signaling in regulating murine sperm functional activity. J Cell Physiol 233:11-22
Wu, Kathie Z; Li, Kun; Galileo, Deni S et al. (2017) Junctional adhesion molecule A: expression in the murine epididymal tract and accessory organs and acquisition by maturing sperm. Mol Hum Reprod 23:132-140
Li, Linqing; Stiadle, Jeanna M; Lau, Hang K et al. (2016) Tissue engineering-based therapeutic strategies for vocal fold repair and regeneration. Biomaterials 108:91-110
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Andrews, Rachel E; Galileo, Deni S; Martin-DeLeon, Patricia A (2015) Plasma membrane Ca2+-ATPase 4: interaction with constitutive nitric oxide synthases in human sperm and prostasomes which carry Ca2+/CaM-dependent serine kinase. Mol Hum Reprod 21:832-43
Hu, Yuan; Sinha, Sudipta Kumar; Patel, Sandeep (2015) Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics. Langmuir 31:6615-31
Smith, Michelle A; Michael, Rowan; Aravindan, Rolands G et al. (2015) Anatase titanium dioxide nanoparticles in mice: evidence for induced structural and functional sperm defects after short-, but not long-, term exposure. Asian J Androl 17:261-8

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