Tom Lynch

Publications

• 15.39

  Impact points

  CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice.

  Weiliang Xie, John T Fisher, Thomas J Lynch, Meihui Luo, Turan I A Evans, Traci L Neff, Weihong Zhou, Yulong Zhang, Yi Ou, Nigel W Bunnett, Andrew F Russo, Michael J Goodheart, Kalpaj R Parekh, Xiaoming Liu, John F Engelhardt

  The Journal of clinical investigation. 08/2011; 121(8):3144-58.

  In cystic fibrosis (CF), a lack of functional CF transmembrane conductance regulator (CFTR) chloride channels causes defective secretion by submucosal glands (SMGs), leading to persistent bacterial infection that damages airways and necessitates tissue repair. SMGs are also important niches for slow... [more] In cystic fibrosis (CF), a lack of functional CF transmembrane conductance regulator (CFTR) chloride channels causes defective secretion by submucosal glands (SMGs), leading to persistent bacterial infection that damages airways and necessitates tissue repair. SMGs are also important niches for slow-cycling progenitor cells (SCPCs) in the proximal airways, which may be involved in disease-related airway repair. Here, we report that calcitonin gene-related peptide (CGRP) activates CFTR-dependent SMG secretions and that this signaling pathway is hyperactivated in CF human, pig, ferret, and mouse SMGs. Since CGRP-expressing neuroendocrine cells reside in bronchiolar SCPC niches, we hypothesized that the glandular SCPC niche may be dysfunctional in CF. Consistent with this hypothesis, CFTR-deficient mice failed to maintain glandular SCPCs following airway injury. In wild-type mice, CGRP levels increased following airway injury and functioned as an injury-induced mitogen that stimulated SMG progenitor cell proliferation in vivo and altered the proliferative potential of airway progenitors in vitro. Components of the receptor for CGRP (RAMP1 and CLR) were expressed in a very small subset of SCPCs, suggesting that CGRP indirectly stimulates SCPC proliferation in a non-cell-autonomous manner. These findings demonstrate that CGRP-dependent pathways for CFTR activation are abnormally upregulated in CF SMGs and that this sustained mitogenic signal alters properties of the SMG progenitor cell niche in CF airways. This discovery may have important implications for injury/repair mechanisms in the CF airway.

• Examination of 5J Coupling in 2,5-disubstituted Dihydrofuroketones

  Tom J. Lynch, Rochelle J. Boote, Jetty L. Duffy-Matzner

  41st Midwest Regional Meeting of the American Chemical Society, Quincy, IL; 10/2006

  Former spectra of novel 2,5-disubstituted dihydrofuroketones have shown interesting 5J coupling. This research will examine the J coupling present in 1-(5-tert-butyl-2-methyl-2,5-dihydrofuran-3-yl) ethanone wherein the ring is substituted with tert-Bu and Me groups. This compd. is synthesized by a v... [more] Former spectra of novel 2,5-disubstituted dihydrofuroketones have shown interesting 5J coupling. This research will examine the J coupling present in 1-(5-tert-butyl-2-methyl-2,5-dihydrofuran-3-yl) ethanone wherein the ring is substituted with tert-Bu and Me groups. This compd. is synthesized by a variety of reactions including Henry Addn., acetylation, deacetylation, Grignard reaction, Michael Addn., and Intramol. Silyl Nitronate Cycloaddn. (ISNC). Examn. of the steric effects of the various substituted functional groups will allow further assessment of the 5J coupling.