Browsing by Subject "plasticity"

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    Phenotypic plasticity in normal breast derived epithelial cells
    (Biomed Central, 2014) Sauder, Candice A. M.; Koziel, Jillian E.; Choi, MiRan; Fox, Melanie J.; Grimes, Brenda R.; Badve, Sunil S.; Blosser, Rachel J.; Radovich, Milan; Lam, Christina C.; Vaughan, Melville B.; Herbert, Brittney-Shea; Clare, Susan E.; Pathology and Laboratory Medicine, School of Medicine
    Background Normal, healthy human breast tissue from a variety of volunteer donors has become available for research thanks to the establishment of the Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center (KTB). Multiple epithelial (K-HME) and stromal cells (K-HMS) were established from the donated tissue. Explant culture was utilized to isolate the cells from pieces of breast tissue. Selective media and trypsinization were employed to select either epithelial cells or stromal cells. The primary, non-transformed epithelial cells, the focus of this study, were characterized by immunohistochemistry, flow cytometry, and in vitro cell culture. Results All of the primary, non-transformed epithelial cells tested have the ability to differentiate in vitro into a variety of cell types when plated in or on biologic matrices. Cells identified include stratified squamous epithelial, osteoclasts, chondrocytes, adipocytes, neural progenitors/neurons, immature muscle and melanocytes. The cells also express markers of embryonic stem cells. Conclusions The cell culture conditions employed select an epithelial cell that is pluri/multipotent. The plasticity of the epithelial cells developed mimics that seen in metaplastic carcinoma of the breast (MCB), a subtype of triple negative breast cancer; and may provide clues to the origin of this particularly aggressive type of breast cancer. The KTB is a unique biorepository, and the normal breast epithelial cells isolated from donated tissue have significant potential as new research tools.
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    Spinophilin Cell Type-Specifically Mediates Metabotrophic Glutamate Receptor 5-dependent Excessive Grooming
    (2022-09) Morris, Cameron W.; Truitt, William; Atwood, Brady; Baucum, Anthony J., II; Ma, Yao-Ying; McKinzie, David
    Compulsive and repetitive behaviors in obsessive-compulsive spectrum disorders (OCSDs) are associated with perturbations in the sensorimotor striatum. Repetitive behaviors are associated with cell type-specific adaptations in striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs, respectively). Furthermore, preclinical models for understanding OCSDs, such as constitutive knockout of disks large associated protein 3 (SAPAP3), suggest repetitive motor dysfunction, such as excessive grooming, is associated with increased metabotropic glutamate receptor 5 (mGluR5) activity that increases dMSN function relative to iMSNs in the sensorimotor striatum. However, MSN subtype-specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Reversible phosphorylation of mGluR5’s C-terminal domain is one mechanism to regulate mGluR5 signaling, however, unlike kinases, promiscuous phosphatases require targeting proteins to shuttle them into contact with their targets. Therefore, phosphatase targeting proteins may be intimately involved in mediating mGluR5-dependent striatal adaptions underlying repetitive behaviors, such as excessive grooming in SAPAP3 deficient mice. Spinophilin, a major striatal postsynaptic phosphatase targeting protein, regulates striatal function, mGluR5 signaling, and forms a protein-protein interaction with SAPAP3 that is increased by mGluR5 co-expression. Therefore, we hypothesized that spinophilin expression in striatal medium spiny neurons mediates mGluR5-dependent excessive grooming. To test this, we used a novel conditional spinophilin mouse line combined with functional, behavioral, and molecular approaches to elucidate spinophilin's MSN subtype-specific contributions to rodent excessive grooming behavior associated with increased mGluR5 function. We found that loss of spinophilin in either MSN subtype abrogated plasticity in the sensorimotor striatum associated with increased mGluR5 function and decreased two models of excessive grooming associated with increased mGluR5 function—SAPAP3 deficient mice and global administration of a mGluR5-specific positive allosteric modulator (VU0360172). Additionally, we found that spinophilin’s protein interaction with mGluR5 correlates with grooming behavior and loss of spinophilin shifts mGluR5 interactions from lipid-raft associated proteins toward postsynaptic density proteins implicated in psychiatric disorders. Collectively, these results identify spinophilin as a novel striatal signaling hub molecule in MSNs that MSN subtype-specifically mediates striatal adaptations associated with repetitive motor dysfunction in psychiatric disorders.