Thomas C Doetschman

Specialist, Embryonic Stem Cell Culture

Member of the General Faculty

Primary Department

BIO5 Institute

Department Affiliations

Cellular & Molecular Medicine

BIO5 Institute

Contact

(520) 626-4901

tdoetsch@u.arizona.edu

Work Summary

I am investigating a human connective tissue disorder in mice. I am also investigating the role of gut bacteria in colon cancer risk in both a mouse model of colon cancer and in humans with colon cancer.

Research Interest

Dr. Thomas Doetschman, PhD, Biochemistry & Biophysics, University of Connecticut, has been involved in cardiovascular research for over a decade through investigations into the cardiovascular roles of the three TGFβ ligands and FGF2 ligand isoforms in genetically engineered mice. These mice have determined that TGFβ2 plays major roles in heart and vascular development and for maintenance of valvular and large vessel integrity in the adult and that both the TGFβ1 and FGF2 are involved in adult heart disease.His work has also demonstrated roles of TGFβ in cancer and immunology. He found that a major function of TGFβ1 is to inhibit autoimmunity and to establish homeostatic balance between immune regulatory and inflammatory cells. He has shown that an imbalance in the latter is critical in the tumor suppressor function of TGFβ in the colon.Dr. Doetschman has also played an important role in the development of the mouse genetic engineering field. He has been responsible for the establishment of 3 mouse genetic engineering facilities, in Cincinnati OH, Singapore and the University of Arizona’s BIO5 Institute. Keywords: "Cancer", "Microbiome", "Mouse Genetic Engineering", "Connective Tissue Disorder"

Publications

The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium.

Doetschman, T., Eistetter, H., Katz, M., Schmidt, W., & Kemler, R. (1985). The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium.. Journal of Embryology and Experimental Morphology, 87, 27-45.

Liver and intestinal fatty acid binding proteins in control and TGF beta 1 gene targeted deficient mice

Fontaine, R., Gossett, R., Schroeder, F., O'Toole, B., Doetschman, T., & Kier, A. (1996). Liver and intestinal fatty acid binding proteins in control and TGF beta 1 gene targeted deficient mice. Molecular and Cell Biochemistry, 159(2), 149-153.

Expression of the lacZ gene targeted to the HPRT locus in embryonic stem cells and their derivatives.

Shaw-White, J., Denko, N., Albers, L., Doetschman, T., & Stringer, J. (1993). Expression of the lacZ gene targeted to the HPRT locus in embryonic stem cells and their derivatives.. Transgenic Research, 2(1), 1-13.

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans

Lidral, A., Romitti, P., Basart, A., Doetschman, T., Leysens, N., Daack-Hirsch, S., Semina, E., Johnson, L., Machida, J., Burds, A., Parnell, T., Rubenstein, J., & Murray, J. (1998). Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. American Journal of Human Genetics, 63(2), 557-568.

2-Photon Characterization of Optical Proteolytic Beacons for Imaging Changes in Matrix-Metalloprotease Activity in a Mouse Model of Aneurysm

Haskett, D. G., Maestas, D., Howerton, S. J., Smith, T., Ardila, D. C., Doetschman, T., Utzinger, U., McGrath, D., McIntyre, J. O., & Vande Geest, J. P. (2016). 2-Photon Characterization of Optical Proteolytic Beacons for Imaging Changes in Matrix-Metalloprotease Activity in a Mouse Model of Aneurysm. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada, 1-12.

Abdominal aortic aneurysm is a multifactorial disease that is a leading cause of death in developed countries. Matrix-metalloproteases (MMPs) are part of the disease process, however, assessing their role in disease initiation and progression has been difficult and animal models have become essential. Combining Förster resonance energy transfer (FRET) proteolytic beacons activated in the presence of MMPs with 2-photon microscopy allows for a novel method of evaluating MMP activity within the extracellular matrix (ECM). Single and 2-photon spectra for proteolytic beacons were determined in vitro. Ex vivo experiments using the apolipoprotein E knockout angiotensin II-infused mouse model of aneurysm imaged ECM architecture simultaneously with the MMP-activated FRET beacons. 2-photon spectra of the two-color proteolytic beacons showed peaks for the individual fluorophores that enable imaging of MMP activity through proteolytic cleavage. Ex vivo imaging of the beacons within the ECM revealed both microstructure and MMP activity. 2-photon imaging of the beacons in aneurysmal tissue showed an increase in proteolytic cleavage within the ECM (p0.001), thus indicating an increase in MMP activity. Our data suggest that FRET-based proteolytic beacons show promise in assessing MMP activity within the ECM and will therefore allow future studies to identify the heterogeneous distribution of simultaneous ECM remodeling and protease activity in aneurysmal disease.

Thomas C Doetschman