UTHSCSA Faculty Profiles v1.0

Fisher, Alfred L

Graduate School of Biomedical Sciences
Barshop Institute

I am a physician-scientist who is both the head of an active basic-science focused research lab, and active in multiple service activities at the Audie L. Murphy VA and on the UTHSCSA campus. These activities include serving as the Associate Director for the MD-PhD program at UTHSCSA, and serving as the Associate Director for Research for the San Antonio GRECC based in the VA. I was recruited to UTHSCSA almost 2 years ago from the University of Pittsburgh where I was similarly active in research and had a larger role in education, including serving as a clerkship director for a required 3rd year Geriatrics clerkship and acting as the education coordinator for Geriatrics within the Internal Medicine residency at the University of Pittsburgh. I chose to leave Pitt despite an attractive retention package so that I could join the much larger Biology of Aging research community at UTHSCSA, which includes such resources as an NIA-funded Nathan Shock center, an NIA-funded Biology of Aging training grant, and a Biology of Aging focused PhD training program, and could also leverage VA resources along with my own NIH grant funding to accelerate research in my lab. The move also better allowed me to align my research and service activities, as many of my service activities utilize my research expertise and skills.

My research uses the nematode C. elegans to study connections between hormone signaling and the aging process. I began this work studying the nuclear hormone receptor daf-12 which both has roles in worm development and in aging. Work both by my lab and others have shown this receptor to be required for normal longevity and to increase longevity when activated. However, the downstream target genes involved in these effects have been a mystery. Both as a post-doctoral fellow and now in my lab, I have worked to identify target genes for this receptor initially via the use of gene expression microarrays and most recently via the use of chromatin immunoprecipitation. The chromatin immunoprecipitation studies proved to be particularly challenging, and I have since learned that competitors attempted them and gave up due to the low expression level and instability of the endogenous protein. My lab was successful in part because of methods we developed to generate transgenic animals using modified genomic DNA fosmids, which allowed us to generate an epitope-tagged form of the receptor. From these studies we learned some principles of how DAF-12 can commit worms to develop either into dauer larvae, a diapause state used in unfavorable environments, or reproductive development. This work was published in PLOS Genetics. Dr. Daniel Hochbaum who played the lead role in this research is now continuing the project in his lab in Argentina.

One pathway which is co-regulated in long-lived daf-12 and daf-2 insulin/IGF-1 mutants is the tyrosine degradation pathway. This is an evolutionarily conserved 5-step pathway which converts tyrosine into energy. My lab has demonstrated that the predicted genes identified by microarray indeed have these biochemical roles in worms, and that the pathway operates similarly in worms as in people. Work by my lab and others have also shown that mutations in or RNAi against the initial genes in the pathway lead to increased longevity. This is likely in part due to reductions in toxic terminal metabolites in the pathway which we have shown lead to proteosomal dysfunction and lead to the activation of the aip-1 (arsenic induced protein) gene. The AIP-1 protein binds to the proteasome to enhance its catalytic activity to attempt to restore protein folding homeostasis. We have shown that aip-1 is under the control of specific transcription factors and have an R01 grant to study aip-1 regulation in more detail.

From our work with aip-1, we and others have found that the expression of the proteasome is under the coordinate control of the Nrf1/2 ortholog skn-1 where decreases in proteasome function lead to the up-regulation of multiple proteasome subunits as a compensatory response. However, the Nrf1/2 transcription factors and skn-1 also control oxidative stress responses, and we have found that there is specificity in the target genes activated by skn-1 in response to these stresses. The cause of this specificity is unclear, and we are using genetics to identify mutants which activate proteasome gene expression to identify upstream genes in the sensing and response pathway. We have also found that low levels of proteasome dysfunction have favorable effects on stress responses and the ability to handle mis-folded proteins. We are currently investigating the involved mechanisms.

The effect of the tyrosine degradation pathway on lifespan also operates via a second pathway as we have found that elevated tyrosine levels serve to activate the daf-16/FOXO transcription factor through novel mechanisms. My lab has studied the effect of tyrosine on daf-16 and found that this occurs downstream of the

7/2013 - Present Associate Professor of Medicine and Associate Professor of Medicine UTHSCSA, Medicine, San Antonio, TX
7/2013 - Present Member of the Medical Staff Audie L. Murphy VA Hospital, Medicine, San Antonio, TX