Our laboratory is focused in two areas of Pharmacology and Therapeutics, including sensory Neuropharmacology and cardiovascular Pharmacology, with work in both the heart and olfactory systems:
- In relation to the olfactory system, our work is devoted to understanding mechanisms of olfaction, pathogenesis of olfactory dysfunction, and the development of curative therapies for anosmia. Olfactory dysfunction in the general population is frequent, affecting at least 2.5 million people in the U.S. alone. In at least 20% of the cases, the etiology of the chemosensory disturbance cannot be identified. We were one of the first to demonstrate olfactory dysfunction as a clinical manifestation of an emerging class of human genetic disorders, termed ciliopathies, which involve defects in ciliary assembly, maintenance, and/or function. Most importantly, we have demonstrated that gene therapy can be used to successfully rescue anosmia resulting from the malformation/loss of cilia. Projects in the laboratory seek to identify direct mechanisms by which sensory input and deprivation regulate olfactory function and to learn how these are disrupted in disease states. Specifically, we work to elucidate the mechanisms underlying the transport of odorant signaling proteins into cilia of olfactory sensory neurons and their alterations in cilia-related disorders. In addition, work completed in the laboratory seeks to understand the importance of cilia for neurogenesis and cell differentiation, investigating their contribution to the regenerative properties of olfactory basal stem cells. Together, this work contributes to our understanding of the pathogenesis of human sensory perception diseases and paves the way for the development of treatments for olfactory loss in humans, where no curative therapies for ciliopathic disease exist.
- In relation to the cardiovascular system, projects in our laboratory are focused on the identification of novel targets for the treatment of cardiac arrhythmias. In particular, we are interested in therapies for atrial fibrillation, which is the most common cardiac arrhythmia, affecting more than 2 million Americans. This electrical instability in the human heart can occur through a primary genetic defect in ion channel function or an acquired disorder attributable to ion channel dysregulation. We are interested in the regulation of voltage-gated potassium (Kv) channels that are vital for atrial repolarization in the human heart. Work in our laboratory is devoted to understanding the details of Kv channel regulation, trafficking, and pharmacological modulation and to learning how this is all integrated into the broader context of normal cardiomyocyte signaling and the pathogenesis of disease.
- Uytingco CR, Green WW, Martens JR. Olfactory loss and dysfunction in ciliopathies: Molecular mechanisms and potential therapies. Curr Med Chem. 2018 Jan 4. doi: 10.2174/0929867325666180105102447.
- Williams CL, Uytingco CR, Green WW, McIntyre JC, Ukhanov K, Zimmerman AD, Shively DT, Zhang L, Nishimura DY, Sheffield VC, Martens JR. Gene Therapeutic Reversal of Peripheral Olfactory Impairment in Bardet-Biedl Syndrome. Mol Ther. 2017 Apr 5;25(4):904-916. doi: 10.1016/j.ymthe.2017.02.006. Epub 2017 Feb 22.
- Chen KS, McIntyre JC, Lieberman AP, Martens JR, Patil PG. Human spinal autografts of olfactory epithelial stem cells recapitulate donor site histology, maintaining proliferative and differentiation capacity many years after transplantation. Acta Neuropathol. 2016 Apr;131(4):639-40. doi: 10.1007/s00401-016-1543-3. Epub 2016 Feb 2.
- Joiner AM, Green WW, McIntyre JC, Allen BL, Schwob JE, Martens JR. Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium. J Neurosci. 2015 Oct 7;35(40):13761-72. doi: 10.1523/JNEUROSCI.1708-15.2015. Erratum in: J Neurosci. 2017 Jun 14;37(24):5974.
- McIntyre JC, Joiner AM, Zhang L, Iñiguez-Lluhí J, Martens JR. SUMOylation regulates ciliary localization of olfactory signaling proteins. J Cell Sci. 2015 May 15;128(10):1934-45. doi: 10.1242/jcs.164673. Epub 2015 Apr 23.
- Williams CL, McIntyre JC, Norris SR, Jenkins PM, Zhang L, Pei Q, Verhey K, Martens JR. Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia. Nat Commun. 2014 Dec 15;5:5813. doi: 10.1038/ncomms6813.