Huge unexplained inter- and intra-laboratory differences in the lifespan of isogenic Atm deficient mice from 2 months to 11.5 months exist in the literature. The intestinal microbiota plays a critical role in our health; in part because these bacteria outnumber the human cells in our body by 10-fold and because they have a huge metabolic capacity. The intricate interplay between the body, especially the immune system, and intestinal microbiota strongly suggests that the intestinal microbiota affects systemic homeostasis. Differences in intestinal microbiota composition are linked to diseases such as obesity, diabetes and behavior. The role of normal, non-pathogenic gut bacteria in carcinogenesis however, is currently unclear.
 

Current Research Projects

Dr. Robert Schiestl‘s Lab has made the striking observation that the nature of gut bacteria significantlyinfluences genetic instability, longevity and lymphoma latency in Atm deficient mice. ATM is important in DNA double-strand break repair, checkpoint control, and redox balance. Atm-/- mice model the human disease ataxia telangiectasia (AT), which is characterized by loss of motor skills, a compromised immune system, and an increased and premature risk of cancer. There is no cure for AT. They kept mice in sterile versus non-sterile environments and in addition specifically tested the contribution of the intestinal microbiota by experimentally changing such microbiota. They showed that isogenic Atm-/- mice have significant variations of DNA deletions at the pun locus between 10 and 43%, they have a significant variation of lifespan between 32 and 51 weeks and the lymphoma latency varied significantly between 25 and 60 weeks under different intestinal flora conditions.

Furthermore, the Schiestl Lab isolated one bacterium Lactobacillus johnsonii from the health beneficial microbiota which by itself significantly reduced genotoxicity, reduced inflammatory cytokines, induced anti-inflammatory cytokines, and reduced the prevalence of natural killer cells, cytotoxic T cells, and CD3 cells in the liver and peripheral blood, which are all linked to inflammation. In addition they found similar differences in P53 deficient mice and even to a lesser extend in wild type mice. Thus, this effect is of general importance. Their findings present an until-now uncharacterized experimental variable, which may have tremendous implications. First in the prevention or delay of lymphoma in AT patients, and secondly for basic research, in which the numerous inter- and intra-laboratory differences in Atm and possibly other cancer predisposed mouse models are in part or entirely explainedby differences in intestinal microbiota. In addition our AT mouse model is hypersensitive to intestinal inflammation. Since inflammation is linked to a host of diseases, such as heart disease, all cancers, neurodegenerative diseases, arthritis, asthma, diabetes, inflammable bowel disease, Crohns disease, and others, bacteria identified in this animal model may benefit as probiotics all those diseases.

Representative Publications:

  • Yamamoto, L. I. Maier , A. T. Dang , D. Berry , J. Liu, P. M. Ruegger , J. Yang, P. A. Soto, L. L. Presley, R. Reliene , A. M. Westbrook , B. Wei , A. Loy , C.r Chang , J. Braun , J. Borneman, R. H. Schiestl (2013) Intestinal bacteria modify lymphoma penetrance in genetically susceptible mice via inflammation-mediated systemic host oxidative stress and leucocyte genotoxicity- Cancer Research 73(14):4222-4232 July 15, 2013 PMCID: PMC3718495
  • Westbrook, A. and R.H. Schiestl (2010) Atm deficient mice exhibit increased sensitivity to dextran sulfate sodium-induced colitis characterized by elevated DNA damage and persistent immune activation. Cancer Research 70, 1875, March 1, 2010. PMCID: PMC2831166

 

Key People

Photo of Laurent Bentolila, PhD
Laurent Bentolila, PhD
Scientific Director, Advanced Light Microscopy/Spectroscopy Lab; Scientific Director, Macro-Scale Imaging Lab; Researcher, California NanoSystems Institute, UCLA
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Address Advanced Light Microscopy/Spectroscopy Laboratory California NanoSystems Institute 570 Westwood Plaza Bldg 114 Los Angeles CA 90095 Phone: (310) 983-1076Website: Laboratory

Dr. Bentolila is a senior researcher at the California NanoSystems Institute (CNSI) at the University of California, Los Angeles (UCLA). He is also the Scientific Director of the Advanced Light Microscopy/Spectroscopy Laboratory (ALMS) and the Macro-Scale Imaging Laboratory (MSI) at CNSI. Dr. Bentolila earned his B.S. in Biochemistry and M.S. in Genetics from Paris-XI University, Orsay and Ph.D. in Molecular Genetics and Immunology from the Pasteur Institute, Paris, France. He was a European Molecular Biology Organization Postdoctoral fellow at the University of California, Berkeley before joining the Department of Chemistry and Biochemistry at UCLA in 2002.

Dr. Bentolila’s long-standing research interest focuses on the application of novel fluorescent probes and advanced microscopy techniques to biology and medicine. Towards this goal, Dr. Bentolila has developed and assembled a unique collection of custom-made and commercial light microscopes for the application of novel spectroscopic methods and advanced microscopy techniques used for the study of macromolecules, cellular dynamics and nano-scale characterization of biomaterials. His most recent research projects include developing new experimental tools for visualizing and tracking cells, bacteria and parasites within a host.

Dr. Bentolila is the recipient of several awards from the Burroughs Wellcome Fund, the European Molecular Biology Organization and the Roux Foundation.

Relevant Recent Publications

  1. Bentolila LA, Prakash R, Mihic-Probst D, Wadehra M, Kleinman HK, Carmichael TS, Péault B, Barnhill RL and Lugassy C. Imaging of Angiotropism/Vascular Co-Option in a Murine Model of Brain Melanoma. Implications for Melanoma Progression along Extravascular Pathways. 2016. Scientific Reports. In press.
  2. Chen AL, Kim EW, Toh JY, Vashisht AA, Rashoff AQ, Van C, Huang AS, Moon AS, Bell HN, Bentolila LA, Wohlschlegel JA and Bradley PJ. Novel components of the Toxoplasma inner membrane complex revealed by BioID. 2015. mBio 6(1) e02357-14.
  3. Kisalu NK, Langousis GD, Bentolila LA, Ralston KS, Hill KL. Mouse infection and pathogenesis by Trypanosoma brucei motility mutants. Cellular Microbiology. 2014. 16(6):912-924.
  4. Mitchell-Jordan S, Chen H, Franklin S, Stefani E, Bentolila LA and Vondriska TM. Features of endogenous cardiomyocyte chromatin revealed by super resolution STED microscopy. J Mol Cell Cardiol. 2012. 53(4):552-8.

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Photo of Dino Di Carlo, PhD
Dino Di Carlo, PhD
Professor, Department of Bioengineering; Member, California NanoSystems Institute, Jonsson Comprehensive Cancer Center
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Address 5121E Engineering V Los Angeles CA 90095 Phone: (310) 983-3235Website: Di Carlo Laboratory

Dino Di Carlo is a Professor in the Department of Bioengineering at UCLA. Over the last 8 years he pioneered using inertial fluid dynamic effects for the control, separation, and analysis of cells in microfluidic devices. His work now extends into numerous fields of biomedicine and biotechnology including directed cellular evolution of microbes, cell and microbial analysis for rapid diagnostics, new amplified molecular assays, next generation biomaterials, and phenotypic drug screening. He also serves as Director of the Cancer Nanotechnology Program of the Jonsson Comprehensive Cancer Center at UCLA and holds a visiting Professorship at the University of Tokyo. He co-founded and currently advises four companies that are commercializing intellectual property developed in his lab over the last six years (CytoVale, Vortex Biosciences, Tempo Therapeutics, and Ferrologix). He has received numerous honors and awards including the Pioneers of Miniaturization Prize in 2015, Analytical Chemistry Young Innovator Award in 2014, the National Science Foundation (NSF) CAREER award, the U.S. Office of Naval Research (ONR) Young Investigator Award, the Packard Fellowship, the Defense Advanced Research Projects Agency (DARPA) Young Faculty Award, the National Institutes of Health (NIH) Director’s New Innovator Award and the Coulter Translational Research Award.

Publications:
Weaver WM, Milisavljevic V, Miller JF, Di Carlo D., “Fluid flow induces biofilm formation in Staphylococcus epidermidis polysaccharide intracellular adhesin-positive clinical isolates,” Appl Environ Microbiol. 2012 Aug;78(16):5890-6. doi: 10.1128/AEM.01139-12. Epub 2012 Jun 15.

Weaver WM, Dharmaraja S, Milisavljevic V, Di Carlo D., “The effects of shear stress on isolated receptor-ligand interactions of Staphylococcus epidermidis and human plasma fibrinogen using molecularly patterned microfluidics,” Lab Chip. 2011 Mar 7;11(5):883-9. doi: 10.1039/c0lc00414f. Epub 2011 Jan 20.

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Photo of Aydogan Ozcan, PhD
Aydogan Ozcan, PhD
Professor, Department of Electrical Engineering and Bioengineering, UCLA; Associate Director, California NanoSystems Institute (CNSI)
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Address 66-127D Engr. IV Los Angeles CA 90095 Phone: (310) 825-0915Website: The Ozcan Research Group

Dr. Ozcan is the Chancellor’s Professor at UCLA and an HHMI Professor with the Howard Hughes Medical Institute, leading the Bio- and Nano-Photonics Laboratory at UCLA School of Engineering and is also the Associate Director of the California NanoSystems Institute (CNSI). Dr. Ozcan holds 32 issued patents (all of which are licensed) and >20 pending patent applications and is also the author of one book and the co-author of more than 400 peer reviewed research articles in major scientific journals and conferences. Dr. Ozcan is a Fellow of SPIE and OSA, and has received major awards including the Presidential Early Career Award for Scientists and Engineers (PECASE), International Commission for Optics (ICO) Prize, SPIE Biophotonics Technology Innovator Award, SPIE Early Career Achievement Award, ARO Young Investigator Award, NSF CAREER Award, NIH Director’s New Innovator Award, ONR Young Investigator Award, IEEE Photonics Society Young Investigator Award and MIT’s TR35 Award for his seminal contributions to near-field and on-chip imaging, and telemedicine based diagnostics. Dr. Ozcan is also the recipient of the National Geographic Emerging Explorer Award, National Academy of Engineering (NAE) The Grainger Foundation Frontiers of Engineering Award, Popular Science Brilliant 10 Award, Gates Foundation Grand Challenges Award, Popular Mechanics Breakthrough Award, Netexplorateur Award, Microscopy Today Innovation Award, and the Wireless Innovation Award organized by the Vodafone Americas Foundation as well as the Okawa Foundation Award.

Publications:
A. Greenbaum, Y. Zhang, A. Feizi, P. Chung, W. Luo, S.R. Kandukuri, and A. Ozcan, ”Wide-field Computational Imaging of Pathology Slides using Lensfree On-Chip Microscopy,” Science Translational Medicine (AAAS) (2014)
DOI:10.1126/scitranslmed.3009850

Q. Wei, W. Luo, S. Chiang, T. Kappel, C. Mejia, D. Tseng, R. Chan, E. Yan, H. Qi, F. Shabbir, H. Ozkan, S. Feng, and A. Ozcan, ”Imaging and Sizing of Single DNA Molecules on a Mobile-Phone,” ACS Nano (2014)
DOI:10.1021/nn505821y

A. Greenbaum, W. Luo, T-W. Su, Z. Göröcs, L. Xue, S.O. Isikman, A.F. Coskun, O. Mudanyali, and A. Ozcan, ”Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nature Methods (2012) DOI:10.1038/nmeth.2114

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Photo of Robert Schiestl, PhD
Robert Schiestl, PhD
Professor, Departments of Pathology and Laboratory Medicine, Environmental Health Sciences, Radiation Oncology, Jonsson Comprehensive Cancer Center, UCLA
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Phone: (310) 267-2087

Robert H. Schiestl has obtained his PhD from the University of Vienna at the age of 23 years. He was postdoctoral fellow at Edmonton, Alberta, Rochester, NY, and Chapel Hill, NC before being professor at Harvard at the age of 31 where he stayed for 10 years. Since 15 years he is professor at UCLA with 187 publications, 10 patents and 2 startup companies.
Intestinal microbiota plays a role in the nutrient metabolism, modulation of the immune system, arthritis, obesity and intestinal inflammation. In the literature there have been huge differences in the same Atm deficient mice in different labs reported. When our lab moved from Harvard to UCLA we found a similar difference in genetic instability and logevity. When we changed the intestinal microbiota back to conventional microbiota we could reproduce the phenotype at Harvard. We tested Atm deficient mice for genotoxicity, genetic instability, DNA damage, inflammation markers, cancer latency and longevity and high throughput sequencing of the intestinal microbiota. Isogenic mice from different housing facilities showed a four fold difference in life expectancy, a 4.5 fold difference in genetic instability and DNA damage. The onset of lymphomas was significantly 2 fold different. We sequenced the microbiota of both facilities and found Lactobacillus johnsonii 456 as dominant bacterial strain in the health beneficial microbiota. Just this bacterium by itself reduced genotoxicity, reduced inflammation and reduced levels of cytotoxic T cells in the liver and blood. We also found similar differences in Trp53 deficient and even in wildtype mice. The underlying mechanisms is probably due to inflammation promotion or suppression mediated by the intestinal microbiota. The understanding of this effect may lead to a breakthrough in the understanding of the causes of carcinogenesis, which might lead to prevention of AT, a currently incurable progressive disease and possibly other cancer-prone DNA repair deficient diseases or even wildtype mice and people.

Relevant Recent Publications

  1. Yamamoto, L. I. Maier , A. T. Dang , D. Berry , J. Liu, P. M. Ruegger , J. Yang, P. A. Soto, L. L. Presley, R. Reliene , A. M. Westbrook , B. Wei , A. Loy , C.r Chang , J. Braun , J. Borneman, R. H. Schiestl (2013) Intestinal bacteria modify lymphoma penetrance in genetically susceptible mice via inflammation-mediated systemic host oxidative stress and leucocyte genotoxicity- Cancer Research 73(14):4222-4232 July 15, 2013 PMCID: PMC3718495
  2. Westbrook, A. and R.H. Schiestl (2010) Atm deficient mice exhibit increased sensitivity to dextran sulfate sodium-induced colitis characterized by elevated DNA damage and persistent immune activation. Cancer Research 70, 1875, March 1, 2010. PMCID: PMC2831166

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