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Faculty
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Daniel E. Michele, Ph.D. dmichele@umich.edu |
Research Interests
My laboratory is interested in the molecular mechanisms of human diseases of skeletal and cardiac muscle. By understanding molecular mechanisms of relatively rare genetic disorders, we hope to shed light on common mechanisms that cause more common idiopathic or acquired forms of skeletal muscle and cardiac disease.
Currently, we are focused on the mechanisms of muscular dystrophy associated with mutations in the transmembrane dystrophin-glycoprotein complex. There has been an explosion of genetic evidence indicating that the central protein in this complex, dystroglycan, is the key player in a number of muscular dystrophies. However, this is not due to primary mutations in dystroglycan itself, but mutations in enzymes that modify the function of dystroglycan as an extracellular matrix receptor. Patients with muscular dystrophy often develop and succumb to cardiomyopathy. The cellular mechanisms of dystroglycan modification and the resulting pathways leading to muscular dystrophy and cardiomyopathy are currently unclear. We are exploring these pathways using spontaneous mutant, traditional and conditional targeted mouse models as well as human patient samples.
In addition, protein complexes containing some of the components of the dystrophin-glycoprotein complex in muscle are expressed throughout the body. Human patients and mouse models with defects in dystroglycan function have altered neuronal migration, synaptic function, peripheral nerve structure and function, eye development and function, and neuromuscular junction formation. We are trying to identify some of the functional ligands of dystroglycan, compensating receptors, and molecules associated with the dystroglycan complex in non-muscle tissues that are necessary for these various non-muscle phenotypes seen in human patients, and whether or not these same molecules have any functional role in skeletal and cardiac muscle disease.
Education
1995 Calvin College, Grand Rapids, MI - B.S., Biology
2000 University of Michigan, Ann Arbor, MI - Ph.D., Physiology
Postgraduate Training
2000-2004 - University of Iowa, Iowa City, IA, Howard Hughes Medical Institute
Mentor: Kevin P. Campbell, Ph.D.
Topic: Post-translation processing of dystroglycan in muscular dystrophy
Honors and Awards
1991-1995 Presidential Scholarship, Calvin College
1991-1995 Dean's List, Calvin College
1993 Karsten Biology Scholarship
1994 Van Oosten Science Division Scholarship
1995 Ten Broek Award for Excellence in Biology Research
1995 John Bean Award for Outstanding Incoming Graduate Student
1996 Horace H. Davenport Award for Outstanding Second Year Graduate Student
1997 Rackham Graduate School Travel Award
1999 Biophysical Society National Meeting Travel Award
1999 University of Michigan Cardiovascular Research Center, Outstanding Poster Presentation/Travel Award
2001 Distinguished Dissertation Award, University of Michigan
2003 Burroughs Wellcome Career Award in Biological Sciences Finalist
2004 University of Michigan Biological Sciences Scholar
2005 Basil O'Connor Scholar, March of Dimes Birth Defects Foundation
Recent Publications
Moore SD, Shilling CJ, Westra S, Wall C, Wicklund MD, Stolle C, Brown CA, Michele, DE, Piccolo F, Winder TL, Stence A, Barresi R, King N, King W, Florence J, Campbell KP, Fenichel GM, Stedman HH, Kissel JT, Griggs RC, Pandya S, Mathews KD, Pestronk A, Serrano C, Darvish D, Mendel JR. Limb-Girdle Muscular Dystrophy in the USA. Journal of Neuropathology and Experimental Neurology. 65(10):995-1003, 2006.
Bhosle RC, Michele DE, Campbell KP, Li Z, Robson RM. Interactions of intermediate filament protein synemin with dystrophin and utrophin. Biochem Biophys Res Commun. 346(3):768-77, 2006.
Kanagawa M, Michele DE, Satz JS, Barresi R, Kusano H, Cohn RD, Sasaki T, Timpl R, Henry MD, Campbell KP. Role of dystroglycan in receptor mediated extracellular matrix organization. FEBS Letters. 436: 1025-1029, 2005.
Yasuda S*, Townsend D*, Michele DE, Favre EG, Day SM, Metzger JM. Dystrophic heart failure blocked by membrane sealant poloxamer. Nature, 579:4792-4796, 2005.
Michele DE, Szatkowski ML, Albayya FP, Metzger JM. Parvalbumin gene delivery improves diastolic function in the aged myocardium. Molecular Therapy. 10: 399-403, 2004.
Kanagawa M*, Saito F*, Kunz S, Yoshida-Moriguchi T, Barresi R, Muschler J, Michele DE, Oldstone MBA, Campbell KP. Molecular recognition by LARGE required for dystroglycan-dependent basement membrane interactions. Cell. 117: 953-964, 2004.
Barresi R, Michele DE, Kanagawa M, Harper HA, Dovico SA, Satz JS, Moore SA, Dumanski JP, Schachter H, Cohn RD, Nishino I, Campbell, KP. LARGE functionally bypasses a-dystroglycan glycosylation defects in congenital muscular dystrophies. Nature Medicine 10: 697-703, 2004.
Kim DS, Hayashi YK, Matsumoto H, Ogawa M, Noguchi S, Murakami N, Mochizuki M, Michele DE, Campbell KP, Nonaka I, Nishino I. Abnormal glycosylation of alpha dystroglycan due to POMT1 gene mutation in a Japanese patient with Walker-Warburg Syndrome. Neurology. 62: 1009-11, 2004.
Lab Projects
Graduate Students
The Michele lab will provide a broad range of training from molecular biology, biochemistry, viral gene transfer, cell biology, and whole animal physiology in the mouse. Any students with interest in the molecular basis of human disease are encouraged to apply. Students will be encouraged and supported to develop their own projects with the goal of first author publications in top tier journals. Please send an email to Dr. Michele including a CV or a brief description of your current status as a student and your experience.
Post Doctoral Position
Title: Molecular Mechanisms of Muscular Dystrophy and Cardiomyopathy
PI: Dr. Daniel Michele, PhD
Contact: 7771 Medical Science II, Department of Physiology, University of Michigan, 48109-0622.
E-mail: dmichele@umich.edu
A post-doctoral position is available to study the molecular mechanisms of human muscular dystrophies and cardiomyopathies associated with mutations in the dystrophin-glycoprotein complex. Spontaneous mutant, gene targeted, and conditional knockout mouse models will be utilized for physiological, cellular, and biochemical/molecular studies of disease processes with a goal of determining possible therapeutic approaches.
Individuals with a post-graduate degree in any biological/biomedical discipline and experience with mouse model development or muscle/cardiovascular research are encouraged to apply.
Please send a CV, a one page summary of research accomplishments and goals, and names/addresses of three references. Electronic submissions by email are preferred.
Additional Lab Links
Useful Links
http://www.physiology.med.umich.edu/research/profiles/dmichele.htm
http://sitemaker.umich.edu/michelelab
Lab Members
Matt Campbell, BS, Graduate Student
Jessica Gumerson, BGS, Graduate Student
Sonya Hovsepian, BS, Research Assistant
Zhyldyz Kabaeva, M.D., Ph.D., Postdoctoral Fellow
Manali Rathod, Undergraduate Assistant