Introduction

Idiopathic diseases (particularly neuro-degenerative and oncologic) continue to make diagnosis and treatment difficult due to their undefined nature. Many of these diseases have a heritable component, and for some, it is the primary underlying etiology. With Whole Exome Sequence from a variety of patients, the identification of a large set of putative disease-causing variants is feasible. The remaining issue is to definitively identify the small set of variants that are truly causative in these polygenic conditions. We utilize new precision medicine pipelines to functionally test combinations of variants in cellular systems.

In the neurosciences, axon degeneration and regeneration are the cellular consequences of debilitating neuropathies and traumatic injuries to the brain and spinal cord.  We and collaborators seek to understand the biological pathway that controls degeneration and regeneration in these important cells.

Sensory Neuropathy

Glaucoma is a subset of neurodegenerative diseases and is extremely common in the US, but the molecular correlates leading to the optic nerve dysfunction is unclear.
Auditory systems in animals consist of a cache of modules which can each be damaged in explosive scenarios or in a number of disorders. We are exploring the role of neuropathy in both Glaucoma and Noise-Induced Hearing Loss.

Autophagy and Disease

In adult cancers, seemingly normal cells respond inappropriately to stress by proliferating and becoming refractory to apoptosis. These cells can be thought of as in a continual state of repair, attempting to heal a wound which they-themselves are creating. Autophagy is one of the cellular processes which is active when cells are in this state-of repair.  Investigating the connections of autophagy after stresses chemotherapy and chronic inflammation will be important to determine how the cells are adapting to these stresses and at which point in the chain of interacting cells is the benefit acquired.

Papers

  • Malapati H, Millen SM, Buchser WJ. The axon degeneration gene SARM1 is evolutionarily distinct from other TIR domain-containing proteins. Mol Genet Genomics. 2017 Aug;292(4):909-922.
  • Wolf S, Swaddle J, Cristol D, Buchser WJMethyl-mercury exposure reduces the auditory brainstem response of zebra finches (Taeniopygia guttata). J Assoc Res Otolaryngol. 2017 Aug;18(4):569-579.
  • Bramley J, Collins S, Clark K, Buchser WJ. Avian Axons Undergo Wallerian Degeneration after Injury and Stress. J Comp Physiol A. 2016 Sep 10. ePub.
  • McInturff S, Buchser W.  A Portable and Inexpensive Device for Recording Evoked Potentials, Optimized for Pattern ERG and Auditory Evoked ResponseBiomedical Techniques. 2015 0042 10.1515/bmt-2015-0042.
  • Beurel E, Harrington L, Buchser W, Lemmon V, Jope R.  Astrocytes Modulate the Polarization of CD4+ T Cells to Th1 Cells.  PLoS One. 2014 Jan 28;9(1):e86257.
  • Buchser W, Collins M, Garyante T, Guha R, Haney S, Lemmon V, Li Z, Trask J.  Assay Development Guidelines for Image-Based High Content Screening, High Content Analysis, and High Content Imaging.  In Assay Guidance Manual, Sittampalam GS, Gal-Edd N, Arkin M, editors.  Bethesda (MD), Oct 2012.
  • Buchser WJ, Smith RP, Blackmore M, Slepak TI, Haddox CL, Pardinas JR, Hoffman S, Bixby JL, Lemmon VP.  Peripheral nervous system genes expressed in central neurons induce growth on inhibitory substrates.  PLoS ONE 7(6): e38101 2012.
  • Buchser WJ, Laskow TC, Pavlik PJ, Lotze MT.  Cell Mediated Autophagy: Induction of Tumor Survival by Lymphocytes. Cancer Res. 2012 May 30. 72(12) 1-10.
  • Liang X, de Vera ME, Buchser WJ, Romo de Vivar Chavez A, Loughran P, Beer-Stolz D, Basse P, Wang T, van Houten B, Zeh HJ, Lotze M. Inhibiting Autophagy During Interleukin 2 Immunotherapy Promotes Long-Term Tumor Regression.  Cancer Res. 2012 Jun 1;72(11):2791-801.
  • Livesey KM, Vernon PJ, Buchser WJ, Loughran P, Kang R, Watkins SC, Zeh HJ, Lotze MT, Tang D. Regulation of autophagy by p53/HMGB1 complexes in Human Colorectal Cancer. Cancer Res. 2012 Apr 15;72(8):1996-2005.
  • Munich S, Sobo-Vujanovic A, Buchser WJ, Beer-Stolz D, Vujanovic NL.  Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands 2012 Dec 1(9).
  • Hutson TH, Buchser WJ, Bixby JL, Lemmon VP, Moon LDF. Optimisation of a 96-well electroporation assay for postnatal rat CNS neurons suitable for cost-effective medium-throughput screening of genes that promote neurite outgrowth.   Mol. Neurosci. 4:55. doi: 10.3389/fnmol.2011.00055.
  • Oudega M, Chao OY, Avison DL, Bronson RT, Buchser WJ, Hurtado A, Grimpe B.  Systemic Administration of a Deoxyribozyme to Xylosyltransferase-1 mRNA Improves Axonal Sprouting/Regeneration and Motor Recovery after a Spinal Cord Contusion Injury in Adult Rats.  Exp Neurol. 2012 Jun 19;237(1):170-179.
  • Lemmon VP, Jia Y, Shi Y, Holbrook SD, Bixby JL, Buchser. Challenges in Small Screening Laboratories: Implementing an On-Demand Laboratory Information Management SystemComb Chem High Throughput Screen. 2011 Jun 1.
  • Chavez AR, Buchser W, Basse PH, Liang X, Appleman LJ, Maranchie JK, Zeh H, de Vera ME, Lotze MT. Pharmacologic administration of interleukin-2. Ann N Y Acad Sci. 2009 Dec;1182:14-27.
  • John E, Laskow TC, Buchser WJ, Pitt B, Basse PH, Butterfield L, Kalinski P, Lotze MT. Zinc Regulates Innate and Adaptive Tumor Immunity.  J Transl Med. 2010 Nov 18;8:118.
  • Buchser WJ, Slepak TI, Gutierrez-Arenas O, Bixby JL, Lemmon VP.  Perturbation of Hippocampal Neurite Outgrowth after Over-expression of Kinase and Phosphatase Genes.  Mol Syst Biol. 2010 Jul;6:391.
  • Moon LDF, Hutson TH, van Kesteren RE, Iffland K, Torres-Muñoz J, Petito CK, Bowen CP, Aimone JB, Buchser WJ, Lemmon VP, Bixby JL, Smit AB, Gage FH, Bunge MB.  A regenerative transcriptome: identification of genes that promote axon regeneration by laser microdissection of in vivo regenerating spinal neurons.
  • Smith RP, Lerch-Haner JK, Pardinas JR, Buchser WJ, Bixby JL, and Lemmon VP.  Transcriptional profiling of intrinsic PNS factors in the postnatal mouse.  Molecular and Cellular Neuroscience.  Mol Cell Neurosci. 2011 Jan;46(1):32-44.
  • Lu Z, Xu Z, Buchser.  Frequency coding of particle motion by saccular afferents of a teleost fish. J Exp Biol. 2010 May;213(Pt 9):1591-601.
  • Lemmon VP, BuchserWJ, Haddox CL, Casciato M, Maggio D, Bixby JL.  Active Learning of Developmental Neuroscience using Original Literature, Public MicroArray Data, Free Software, and Exercises in Data Clustering and Experimental Design. 2010.
  • Smith RP, BuchserWJ, Lemmon MB, Pardinas JR, Bixby JL, Lemmon VP.  EST Express: PHP/MySQL based automated annotation of ESTs from expression libraries.  BMC Bioinformatics. 2008 Apr 10; 9:186.
  • BuchserWJ, Pardinas JR, Shi Y, Bixby JL, Lemmon VP.  Efficient and Inexpensive 96-Well Electroporation Method for Transfection of Mammalian Central Neurons.  Biotechniques 2006 Nov; 41(5): 619-24.
  • Porciatti V, Sorokac N, BuchserHabituation of Retinal Ganglion Cell Activity in Response to Steady-State Pattern Visual Stimuli in Normal Subjects.  IOVS 2005 Apr; 46(4): 1296-302.
  • Lu Z, Xu Z, BuchserCoding of acoustic particle motion by utricular fibers in the sleeper goby, Dormitator latifrons.  J Comp Physiol A. 2004 Nov; 190(11): 923-38.
  • Lu Z, Xu Z, BuchserAcoustic response properties of lagenar nerve fibers in the sleeper goby, Dormitator latifrons.  J Comp Physiol A. 2003 Dec; 189(12): 889-905.

Neuroscience

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