Bruce J. Nicholson, PhD

Research

Structure and function of gap junctions

The Nicholson laboratory uses a combination of techniques to investigate the role of direct intercellular communication by gap junctions in various biological processes, both normal and pathogenic, including cancer, deafness, endometriosis and inflammatory responses to infection. In order to understand the underlying molecular basis of how the sharing of metabolites and signals between cells can modify their behavior, we have been characterizing the selective permeability of the different members of the connexin family to signaling molecules, and how they are regulated in pathogenic processes like cancer (Polusani et. al., 2019; Mitra et. al., 2012).

We are using this information to dissect out the role played by gap junctions in various disease processes, including controlling the growth of cancer cells (Chandrasekhar et. al., 2013), yet promoting their motility during metastasis (Polusani et. al., 2016), and understanding the analogous, but benign invasive processes in endometriosis. We have also characterized the passage of larger molecules, like peptides and miRNAs through gap junctions, and assessing if this can explain the propagation of damaging inflammatory responses in Chlamydia infections that can lead to infertility (Vivek et.al.,2015).

Current Projects:

Connexin profiles as a diagnostic of endometriosis: Analysis of gene expression profiles of endometrial patient samples, using single cell profiling in the BASiC Facility (http://molecularmedicine.uthscsa.edu/research.aspx) has revealed a reproducible fingerprint of progressive changes in connexin expression as endometriosis develops. We are focusing on expanding these analyses to investigate the extent to which endometriosis originates in the uterus, and as a non-invasive diagnostic.

Functional roles of gap junctions in endometriosis: Initial in vitro measures of cellcoupling and invasiveness of primary endometrial cells from endometriosis patients and normal subjects implicates an induction of gap junction coupling between the endometrial cells and the peritoneal mesothelium is required for the invasive process. We are currently characterizing this process with the objective of developing a novel therapeutic strategy that could benefit millions of women worldwide. (with N. Kirma, Dept.Molecular Medicine)

Awards & Accomplishments

1988-92: PEW Scholar
1992-97 AHA Established Investigator
1993-96: Max Planck Prize
2001-05: Editor-in Chief: Cell Communication and Adhesion
2003-05: Member, Faculty of 1000
2003-pres:Member, Council for Canadian Chairs
2008-12: Executive Committee-CTRC
2012-pres:Internal Advisory Board-CTRC

Publications

• Polusani, S, Huang, Y-W, Huang, G, Chen, C-W, Wang, C-M, Lin, L-L, Osmulski, P, Lucio, N, Liu, L, Hsu, Y-T, Zhou, Y, Lin, C-L, IAguilera-Barrantes, I, Valente, P, Kost, E, Chen, C-L, Shim, E-Y, Lee, SE, Ruan, J, Gaczynska, M, Yan, P, Goodfellow, P, Mutch, D, Jin, V, Nicholson, BJ, Huang, T, and Kirma, N.  Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction loci in obese endometrial cancer. Cancer Res. 79: 196-208 (2019) PMID 30389702

• Nielsen, BS, Alstrom, JS, Nicholson, BJ, Nielsen, MS and MacAulay, N. Permeant-specific gating of connexin 30 hemichannels. J. Biol Chem 292: 19999-20009 (2017) PMID 28982982

• Polusani, SR, Kalmykov, EA, Chandrasekhar, A, Zucker, SN and Nicholson BJ. Connexin 26 gap junction coupling selectively contributes to reduced adhesivity and increased cell migration. J. Cell Sci 129:4399-4410 (2016)  PMID 27777264

• Vivek, KR, Li W, Manam S, Zanoti B, Nicholson, BJ, Ramsey KH, Murthy AK. The contribution of Chlamydia-specific CD8+/- T cells to upper genital tract pathology. Immunol Cell Biol. 9: 208-212 (2015). PubMed PMID: 26323581.

• Chandrasekhar, A., Kalmykov, E., Polusani, S.R., Mathis, S., Zucker, S., and Nicholson, B.J. Intercellular redistribution of cAMP through gap junctions underlies the selective suppression of HeLa cell growth by Cx26  PLoS ONE 8: e82335. doi:10.1371 (2013) PMID 243126555

• Mitra, S., Xu, J. and Nicholson, B.J. Co-regulation of multiple signaling mechanisms in pp60v-src induced closure of Cx43 Gap junction channels. J. Memb. Biol. 245: 495-506. (2012) PMID: 22965738, LINK: Coregulation of multiple signaling mechanisms in pp60v-Src-induced closure of Cx43 gap junction channels.

• Xu J, Nicholson B.J.  Biochim Biophys Acta: 2012-07-13; (); Epub: 2012-07-13. PMID: 22796187,  LINK: The role of connexins in ear and skin physiology – Functional insights from disease-associated mutations.

• Oshima A, Tani K, Toloue MM, Hiroaki Y, Smock A, Inukai S, Cone A, Nicholson BJ, Sosinsky GE, Fujiyoshi Y,  J Mol Biol: 2011-01-21; 405(3); 724-35; Epub: 2010-11-20. PMID: 21094651, LINK: Asymmetric configurations and N-terminal rearrangements in connexin26 gap junction channels.

• Liu J, Xu J, Gu S, Nicholson BJ, Jiang JX; J Cell Sci: 2011-01-15; 124(Pt 2); 198-206; Epub: 2010-12-20. PMID: 21172802, LINK: Aquaporin 0 enhances gap junction coupling via its cell adhesion function and interaction with connexin 50.

• Toloue MM, Woolwine Y, Karcz JA, Kasperek EM, Nicholson BJ, Skerrett IMCell Commun Adhes: 2008-05-01; 15(1); 95-105. PMID: 18649182, LINK: Site-directed mutagenesis reveals putative regions of protein interaction within the transmembrane domains of connexins.