Ronald M Lynch
Associate Director, Shared Resources
Associate Professor, Pharmacology
Director, Aribi Institute
Professor, BIO5 Institute
Professor, Biomedical Engineering
Professor, Physiological Sciences - GIDP
Professor, Physiology
Primary Department
Department Affiliations
(520) 626-2472
Work Summary
Precise diagnosis and treatment of disease requires an ability to target agents to specific tissues and cell types within those tissues. We are developing agents that exhibit cell type specificity for these purposes.
Research Interest
Ron Lynch received a B.S. from the University of Miami (1978) with a dual major in Chemistry (Physical) and Biology, and a Ph.D. degree from the University of Cincinnati (1984) in Physiology and Biophysics. Dr. Lynch began training in optical imaging and MR spectroscopy of cardiac metabolism while at the NIH/NHLBI under the direction of Dr. Robert Balaban from 1984-1987. In 1987, Dr. Lynch moved to a staff position in the Biomedical Imaging Group with appointment in the Physiology Department at the University of Massachusetts Medical Center where he was involved in the development of approaches for 3-dimensional imaging including deconvolution and confocal microscopy. Dr. Lynch joined the faculty of the University of Arizona in 1990 with dual appointment in the Departments of Physiology and Pharmacology, and is currently a full professor, and director of the Arizona Research Institute for Biomedical Imaging. In 2000, Dr. Lynch was a visiting scientist at the Laboratory of Functional and Molecular Imaging and the Magnetic Resonance Imaging Center with Dr. Alan Koretsky at the NIH/NINDS. Dr. Lynch is a member of the Biophysical Society, the American Physiological Society and American Diabetes Association, and regularly serves on grant review panels for the JDRF, NIH/NIDDK, and NSF. Research in the Lynch lab focuses on second messenger signaling in vascular smooth muscle cells and nutrient sensing cells (e.g., Pancreatic Beta-cells) with emphasis on alterations in signaling that occur during development of Diabetes. We are developing methods to modify and analyze beta cell mass in order to evaluate the initiation of the pre-diabetic state, and efficacy of its treatment. Analyses of subcellular protein distributions, second messenger signaling, and ligand binding is performed in our lab using state of the art microscopy and analysis approaches which is our second area of expertise. Over the past 3 decades, our lab has been involved in the development of unique microscopic imaging and spectroscopy approaches to study cell and tissue function, as well as screening assays for cell signaling and ligand binding. Keywords: Diabetes, Cancer, Optical Imaging, Targeted Contrast Agents, Metabolism, Biomedical Imaging, Drug Development

Publications

Smith, K. E., Kelly, A. C., Min, C. G., Weber, C. S., McCarthy, F. M., Steyn, L. V., Badarinarayana, V., Stanton, J. B., Kitzmann, J. P., Strop, P., Gruessner, A. C., Lynch, R. M., Limesand, S. W., & Papas, K. K. (2017). Acute Ischemia Induced by High-Density Culture Increases Cytokine Expression and Diminishes the Function and Viability of Highly Purified Human Islets of Langerhans. Transplantation, 101(11), 2705-2712.
BIO5 Collaborators
Sean W Limesand, Ronald M Lynch

Encapsulation devices have the potential to enable cell-based insulin replacement therapies (such as human islet or stem cell-derived β cell transplantation) without immunosuppression. However, reasonably sized encapsulation devices promote ischemia due to high β cell densities creating prohibitively large diffusional distances for nutrients. It is hypothesized that even acute ischemic exposure will compromise the therapeutic potential of cell-based insulin replacement. In this study, the acute effects of high-density ischemia were investigated in human islets to develop a detailed profile of early ischemia induced changes and targets for intervention.

Steyn, L. V., Ananthakrishnan, K., Anderson, M. J., Patek, R., Kelly, A., Vagner, J., Lynch, R. M., & Limesand, S. W. (2015). A Synthetic Heterobivalent Ligand Composed of Glucagon-Like Peptide 1 and Yohimbine Specifically Targets β Cells Within the Pancreas. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.
BIO5 Collaborators
Sean W Limesand, Ronald M Lynch

β Cell specificity for a heterobivalent ligand composed of glucagon-like peptide-1 (GLP-1) linked to yohimbine (GLP-1/Yhb) was evaluated to determine its utility as a noninvasive imaging agent.

Limesand, S., Green, A. S., Chen, X., Macko, A. R., Anderson, M. J., Kelly, A. C., Hart, N. J., Lynch, R. M., & Limesand, S. W. (2012). Chronic pulsatile hyperglycemia reduces insulin secretion and increases accumulation of reactive oxygen species in fetal sheep islets. The Journal of endocrinology, 212(3).
BIO5 Collaborators
Sean W Limesand, Ronald M Lynch

Children from diabetic pregnancies have a greater incidence of type 2 diabetes. Our objective was to determine if exposure to mild-moderate hyperglycemia, by modeling managed diabetic pregnancies, affects fetal β-cell function. In sheep fetuses, β-cell responsiveness was examined after 2 weeks of sustained hyperglycemia with 3 pulses/day, mimicking postprandial excursions, and compared to saline-infused controls (n = 10). Two pulsatile hyperglycemia (PHG) treatments were studied: mild (mPHG, n = 5) with +15% sustained and +55% pulse; and moderate (PHG, n = 10) with +20% sustained and +100% pulse. Fetal glucose-stimulated insulin secretion and glucose-potentiated arginine insulin secretion were lower (P

Hart, N. J., Chung, W. J., Weber, C., Ananthakrishnan, K., Anderson, M., Patek, R., Zhang, Z., Limesand, S. W., Vagner, J., & Lynch, R. M. (2013). Hetero-bivalent GLP-1/Glibenclamide for Targeting Pancreatic β-Cells. Chembiochem : a European journal of chemical biology.
BIO5 Collaborators
Sean W Limesand, Ronald M Lynch

G protein-coupled receptor (GPCR) cell signalling cascades are initiated upon binding of a specific agonist ligand to its cell surface receptor. Linking multiple heterologous ligands that simultaneously bind and potentially link different receptors on the cell surface is a unique approach to modulate cell responses. Moreover, if the target receptors are selected based on analysis of cell-specific expression of a receptor combination, then the linked binding elements might provide enhanced specificity of targeting the cell type of interest, that is, only to cells that express the complementary receptors. Two receptors whose expression is relatively specific (in combination) to insulin-secreting pancreatic β-cells are the sulfonylurea-1 (SUR1) and the glucagon-like peptide-1 (GLP-1) receptors. A heterobivalent ligand was assembled from the active fragment of GLP-1 (7-36 GLP-1) and glibenclamide, a small organic ligand for SUR1. The synthetic construct was labelled with Cy5 or europium chelated in DTPA to evaluate binding to β-cells, by using fluorescence microscopy or time-resolved saturation and competition binding assays, respectively. Once the ligand binds to β-cells, it is rapidly capped and presumably removed from the cell surface by endocytosis. The bivalent ligand had an affinity approximately fivefold higher than monomeric europium-labelled GLP-1, likely a result of cooperative binding to the complementary receptors on the βTC3 cells. The high-affinity binding was lost in the presence of either unlabelled monomer, thus demonstrating that interaction with both receptors is required for the enhanced binding at low concentrations. Importantly, bivalent enhancement was accomplished in a cell system with physiological levels of expression of the complementary receptors, thus indicating that this approach might be applicable for β-cell targeting in vivo.

Kelly, A. C., Camacho, L. E., Pendarvis, K., Davenport, H. M., Steffens, N. R., Smith, K. E., Weber, C. S., Lynch, R. M., Papas, K. K., & Limesand, S. W. (2018). Adrenergic receptor stimulation suppresses oxidative metabolism in isolated rat islets and Min6 cells. Molecular and cellular endocrinology.
BIO5 Collaborators
Sean W Limesand, Ronald M Lynch

Insulin secretion is stimulated by glucose metabolism and inhibited by catecholamines through adrenergic receptor stimulation. We determined whether catecholamines suppress oxidative metabolism in β-cells through adrenergic receptors. In Min6 cells and isolated rat islets, epinephrine decreased oxygen consumption rates compared to vehicle control or co-administration of epinephrine with α2-adrenergic receptor antagonist yohimbine. Epinephrine also decreased forskolin-stimulated oxygen consumption rates, indicating cAMP dependent and independent actions. Furthermore, glucose oxidation rates were decreased with epinephrine, independent of the exocytosis of insulin, which was blocked with yohimbine. We evaluated metabolic targets through proteomic analysis after 4 h epinephrine exposure that revealed 466 differentially expressed proteins that were significantly enriched for processes including oxidative metabolism, protein turnover, exocytosis, and cell proliferation. These results demonstrate that acute α2-adrenergic stimulation suppresses glucose oxidation in β-cells independent of nutrient availability and insulin exocytosis, while cAMP concentrations are elevated. Proteomics and immunoblots revealed changes in electron transport chain proteins that were correlated with lower metabolic reducing equivalents, intracellular ATP concentrations, and altered mitochondrial membrane potential implicating a new role for adrenergic control of mitochondrial function and ultimately insulin secretion.