Investigators

Bruno Conti, Ph.D.

Professor
Aging and Age Associated Diseases
858-434-1961

Research Focus

Our laboratory uses a combination of genetic, pharmacological and molecular approaches to investigate in the mouse the mechanisms of neurodegenerative diseases and the neuronal regulation of temperature homeostasis and its role in aging. Specifically, we focus on: 1. The neuroimmunology of cytokines and their role in regulating neuronal survival and functions; 2.The role of temperature in the biology of aging.

Cloning Interleukin 18 (IL-18) and characterization of its role as neuro-immunomodulator.
In 1997 we cloned interferon-gamma inducing factor, subsequently officially named interleukin 18 (IL-18), from the adrenal gland and demonstrated its expression also in the central nervous system. Over several years we showed that IL-18 is a cytokine that can be produced in the central nervous system either during inflammation or during stress. The distribution of its receptors in neurons throughout the brain indicates that this molecule can affect neuronal function, a hypothesis at least in part demonstrated by us for the ability of IL-18 to regulate feeding and sickness behavior by acting on neurons of the bed nucleus of the stria terminalis. In addition, IL-18 also appears to be able to modulate neuroinflammation contributing to neuronal damage.

The neuroimmunology of interleukin 13 (IL-13) and its role in Parkinson’s Disease. We identified IL-13 and its receptor alpha 1 (IL-13Ra1) as factors that contribute to the onset and/or the progression of Parkinson’s disease (PD). We demonstrated that in the brain IL-13Rα1 was exclusively expressed in dopaminergic neurons that are lost in PD and that IL-13 could be induced locally by neurons and glial cells. We found that activation of IL-13Rα1 signaling could potentiate cellular susceptibility to otherwise non-toxic levels of reactive oxidative species. These data convinced us that IL-13 and IL-13Rα1 can affect survival of dopaminergic neurons that are lost in PD and prompted us to investigate the possible implications and applications of our findings. In vitro, that the ability of IL-13 to potentiate oxidative-mediated damage can be inhibited by blocking either the Jak-Stat or the PI3 kinase-mTOR signaling activated by IL-13Rα1. Among them are rapamycin and ruxolitinib, two FDA approved drugs. Our findings provide a rationale for testing the effects of ruxolitinib in slowing the progression of PD. They also indicate that regenerative medicine for PD may need to consider developing iPSC derived neurons depleted of IL-13Rα1 which would otherwise serve as a death signal re-exposing the transplanted cells to the same vulnerability of the parental ones.

2. Central Regulation of Temperature Homeostasis and the Biology of Aging.
Age is the main risk factor for the development of neurodegenerative diseases and, as such, investigating its biology is one step towards deciphering the mechanisms of neurodegeneration. To date, the only intervention showed to retard aging is balanced reduction of calorie intake (now known as calorie restriction, CR). CR causes a reduction of core body temperature (Tb) and we were able to demonstrate that lowered Tb contributed to the beneficial effects of CR. We also identified some of the molecules and the neuronal circuitry that regulate Tb reduction during CR. These include the hypothalamic insulin-like growth factor receptor (IGF-1R) and the kappa opioid receptor. Ongoing investigation is aimed at identifying the genetic and the biochemical pathways that mediate the effects of temperature on longevity. We hope that these will represent targets for generating “temperature mimetics” to treat aging and age-associated diseases including neurodegeneration.


Education

Ph.D. in Biological Sciences, University of Milan, 1991
Ph.D. in Pharmacology and Physiology, University of Modena, 2011


Professional Experience

2022 – Present Professor, San Diego BioMed
2022 – Present, Professor Emeritus, Molecular Medicine/Neuroscience, The Scripps Research Institute
2018 – Present, Adjunct Professor, Biochemistry & Biophysics, University of Stockholm
2013, Visiting Professor, University of Modena, Italy
2012, Visiting Professor, Stockholm University, Sweden
2010 – 2018, Investigator, Dorris Neuroscience Center, The Scripps Research Institute
2010 – 2022, Professor, Molecular Medicine/Neuroscience, The Scripps Research Institute
2008 – 2010, Associate Professor with Tenure, Molecular and Integrative Neuroscience, The Scripps Research Institute


Honors and Awards

Ellison Medical Foundation Senior Scholar in Aging, 2006
Italian Ministry for Scientific Research Fellowship Award, 1992


Professional Activities

2016 – 2021 Chair, Italian Scientists and Scholar in North America Foundation San Diego Chapter
Member, American Federation for Aging Research, National Scientific Advisory Council
Member, International Society of Neuroimmunology
Member, New York Academy of Sciences
Member, Society for Neuroscience
Member, Lifeboat Foundation Scientific Advisory Board

Select Publications

Conti, B., Sanchez-Alavez, M., Winsky-Sommerer, R., Morale, M. C., Lucero, J., Brownell, S., Fabre, V., Huitron, Resendiz, S., Henriksen, S., Zorrilla, E. P., de Lecea, L. & Bartfai, T. Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825-828 (2006).

Morrison, B. E., Marcondes, M. C., Nomura, D. K., Sanchez-Alavez, M., Sanchez-Gonzalez, A., Saar, I., Kim, K. S., Bartfai, T., Maher, P., Sugama, S. & Conti, B. Cutting Edge: IL-13Ralpha1 Expression in Dopaminergic Neurons Contributes to Their Oxidative Stress-Mediated Loss following Chronic Peripheral Treatment with Lipopolysaccharide. J Immunol 189, 5498-5502 (2012).

Conti, B. & Hansen, M. A Cool Way to Live Long. Cell 152, 671-672 (2013).

Cintron-Colon, R., Sanchez-Alavez, M., Nguyen, W., Mori, S., Gonzalez-Rivera, R., Lien, T., Bartfai, T., Aid, S., Francois, J. C., Holzenberger, M. & Conti, B. Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction. Proc Natl Acad Sci U S A 114, 9731-9736 (2017).

Aguirre, C. A., Morale, M. C., Peng, Q., Sanchez-Alavez, M., Cintrón-Colón, R., Feng, K., Fazelpour, S., Maher, P. & Conti, B. Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson’s disease increase cellular susceptibility to oxidative stress. Brain Behav Immun Available online 7 April 2020 (2020).

Conti, B. Hot news about temperature and lifespan. Nature Metabolism (2022) (In press)

All of Dr. Bruno Conti’s Publications

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Our research programs are funded primarily by grants from the National Institutes of Health (NIH). Private donations help to accelerate the progress of research through the purchase of laboratory supplies and equipment or the recruitment of additional laboratory personnel. Thank you!

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