Current Research
The goal of Dr. Clare-Salzler’s laboratory is to define the immunopathogenesis of type-1 diabetes. To accomplish this goal Dr. Clare-Salzler studies immune cells from the non obese diabetic (NOD) mouse and from humans with a defined high-risk for type-1 diabetes. His laboratory has focused many of their studies on the biology of antigen presenting cell populations, e.g. macrophages and dendritic cells and determining their role in the immunopathogenesis of this disease. Studies to date indicate that dendritic cells presenting islet antigens impart tolerance and block the development of autoimmune disease in the NOD mouse. Other studies indicate defects in myeloid cells, including monocytes, macrophages, and myeloid dendritic cells contribute to the pathogenesis of this disease. In addition, studies in his laboratory indicate defects in activation induced cell death, a critical mechanism of peripheral tolerance, in both NOD mice and in humans with a risk for type-1 diabetes.
To determine the genetic contributions to the immunophenotypes described above Dr. Clare-Salzler’s laboratory is examining these in congenic mice with defined regions of NOD chromosomes on the C57BL/6 background. This analysis allows one to determination which regions NOD chromosomes controls the immunophenotype, e.g. defective deletional tolerance.
Using this approach the laboratory defined an abnormal expression of cyclooxygenase II (Cox II) in monocytes and macrophages which leads to heightened prostaglandin metabolism in the NOD mouse and also in humans who are at risk for type-1 diabetes. Analysis of Cox II in macrophages of congenic mice indicates that this phenotype is controlled by two trans-activating genes from two separate regions of mouse chromosome 1. The generation of new congenic strains with shorter intervals will allow for eventual identification of the genes responsible for this phenotype by positional cloning. The same approach has also defined two regions of the NOD genome that contribute to the defects in deletional tolerance, one in a region on mouse chromosome 17, perhaps the MHC or a gene(s) within this region, and another contained on chromosome 1.
NAME
Michael Clare-Salzler,
M.D. POSITION TITLE
Associate
Professor
EDUCATION/TRAINING
| INSTITUTION AND LOCATION | DEGREE | YEAR(s) | FIELD OF STUDY |
| University of Notre Dame, Notre Dame, IN | B.S. | 1971-1975 | Chemistry |
| S.U.N.Y. Buffalo School of Medicine, Buffalo, NY | M.D. | 1975-1979 | Medicine |
| S.U.N.Y. Buffalo Affiliated Hospitals, Buffalo, NY | 1979-1982 | Internal Medicine Residency | |
| UCLA School of Medicine, Los Angeles, CA | 1985-1988 | Research Fellowship |
Professional Experience
Director,
Dillon Health and Treatment, Dillon, Colorado, 1981-1983
Staff, St.
Anthony's Hospital System, Denver, Colorado, 1983-1985
Staff, Frisco
Medical Center, Frisco, Colorado, 1983-1985
Research
Fellow, Division of Endocrinology, UCLA School of Medicine, 1985-1988
Director,
UCLA Diabetes Clinic, 1989-1993
Assistant
Professor of Medicine, UCLA School of Medicine, Division of Endocrinology,
1988-1993
Assistant
Professor Department of Pathology & Laboratory Medicine/Internal Medicine,
University of Florida, College of Medicine, 1993-1997
Associate
Professor of Pathology and Laboratory Medicine/Medicine/Surgery, University
of Florida, College of Medicine, 1997-Present
Director,
Department of Pathology SPF Mouse Facility, 1997-present
Honors/Memberships
Cum Laude,
University of Notre Dame.
NIH Clinical
Investigator Research Award, 1988
Special NIH
Study Section, 1997
Vice Chair,
DPT-1 Ancillary Studies and Publication Committees, 1995-present
Ad Hoc Member
for the DPT-1 Steering Committee, 1995-present
Juvenile
Diabetes Foundation
American
Diabetes Association
Selected Publications
1. Mullen,
Y., Taura, Y., Clare-Salzler, M., et al. Reversal of experimental
diabetes in miniature swine of fetal pancreas allografts. Transplantation
Proceedings 21:2671-72, 1989.
2.
Terada, M., Clare-Salzler, M., Lennartz, K., Mullen, Y. The Effects
of H-2 Compatibility on Pancreatic Beta cell survival in the non-obese
diabetic mouse. Transplantation 45:622-27, 1988.
3.
Yoneda, K., Mullen, Y., Stein, E., Clare-Salzler, M., et al. Fetal
pancreas transplantation in miniature swine II survival of fetal pig pancreas
allografts Cultured at room temperature. Diabetes 38(suppl 1):213,
1989.
4.
Mullen, Y., Clare-Salzler, M., Stein, E., Clark, W. Conference Report:
Islet transplantation for the cure of diabetes. Pancreas 4:123-35,
1989.
5.
Nagata, M., Mullen, Y., Matsuo, S., Herrera, M., Clare-Salzler, M.
Destruction of islet isografts by severe nonspecific inflammation.
Transplantation Proceedings 22:855, 1990.
6.
Clare-Salzler M.J., Van Herle A.J., Varki N.M., Tillisch J. Endocardial
metastases of follicular thyroid carcinoma: a case report and review of
the literature. Eur J Surg Oncol 17(2):219-23, 1991.
7.
Jacobs EL, Clare-Salzler MJ, Chopra IJ, Figlin RA. Thyroid function
abnormalities associated with the chronic outpatient administration of
recombinant interleukin-2 and recombinant interferon-alpha. J Immunother
10(6):448-55, 1991.
8.
Kaufman, D., Clare-Salzler, M., Atkinson, et al. Autoimmunity to
two forms of glutamate decarboxylase in insulin dependent diabetes mellitus.
Journal of Clinical Investigation 89:283-292, 1992.
9.
Clare-Salzler, M., Kaufman, D., Tobin, A. Glutamate decarboxylase on IDDM
autoantigen. Diabetes Care 15:132-35, 1992.
10.
Clare-Salzler, M., Mullen, Y. Marked dendritic cell-T cell cluster
formation in the pancreatic lymph node of the non-obese diabetic mouse.
Immunology 76:478-84, 1992.
11.
Clare-Salzler, M., Brooks, J., Van Herle, K., et al. Prevention of diabetes
in NOD mice by dendritic cell transfers. Journal of Clinical Investigation
90:741-48, 1992.
12.
Gottschalk, M., Schatz, D.E., Clare-Salzler, M., et al. Permanent non-autoimmune
diabetes following transient neonatal diabetes. Diabetes Care 15:1273-1276,
1992.
13.
Geffner M.E., Clare-Salzler M., Kaufman D.L., Ting G.S., Gottschalk M.E.,
Schatz D.A. Permanent diabetes developing after transient neonatal diabetes.
Lancet 341(8852):1095,1993.
14.
Kaufman, D.L., Clare-Salzler, M., Tian, J., et al. Spontaneous loss of
T cell tolerance to glutamate decarboxylase is a key event in the pathogenesis
of Murine insulin-dependent diabetes. Nature 366:69-72, 1993.
15.
Deng, H., Apple, R. Clare-Salzler, M., Trembleau, S.,et al. Determinant
capture as a possible mechanism of protection afforded by major histocompatibility
complex class II molecules in autoimmune disease. Journal of Experimental
Medicine 178:1675-80, 1993.
16.
Clare-Salzler, M., Mullen, Y., Chai, A., et al. Effect of H-2 compatibility
in autoimmune destruction of islet allografts from B10 congenic lines to
nonobese diabetic mice. Pancreas 9:179-85, 1994.
17.
Muir, A., Peck, A., Clare-Salzler, M., et al. Insulin immunization of NOD
mice induces a protective insulitis characterized by diminished intra-islet
interferon-gamma transcription. Journal of Clinical Investigation
95:628-34, 1995.
Neurochem
Res 1995 Jul;20(7):869-73
18.
Cornford E.M., Hyman S., Cornford M.E., Clare-Salzler M. Down-regulation
of blood-brain glucose transport in the hyperglycemic nonobese diabetic
mouse. Neurochem Res 20(7):869-73, 1995.
19.
Benhamou, P.Y., Mulen, Y., Clare-Salzler, M., et al. Essential fatty acid
deficiency prevents autoimmune diabetes in non obese diabetic mice through
a positive impact on antigen presenting cells and Th2 lymphocytes. Pancreas
11;26, 1995.
20.
Tian, J., Atkinson, M.A., Clare-Salzler, M., Herschenfeld, A., et al. Nasal
administration of glutamate decarboxylase (GAD65) peptides induces a Th2
and prevents murine insulin dependent diabetes. J Exp Med 183:1561-67,
1996.
21.
Tian, J., Clare-Salzler, M., Herschenfeld, A., Middleton, B., et al. Modulating
autoimmune responses to GAD inhibits disease progression and prolongs islet
graft survival in diabetes-prone mice. Nature Medicine, 2:1348-53,
1996.
22.
Solorzano, C.C., Ksontini, R., Pruitt,J., Clare-Salzler, M., et al. Involvement
of 26kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation
of liver injury with a matrix metalloproteinase inhibitor. Journal
of Immunol 158(1):414-19, 1997.
23.
Guilig, P.A., Doyle,T.J. Clare-Salzler, M.J., et al: Systemic infection
of mice by wild -type but no SPV-Salmonella typhinurium is enhanced by
neutralization of interferon-y and tumor necrosis factor alpha. Infect.
Immun. 65:5191, 1997
24. Ksontini,
R., Colagiovanni, D.B., Edwards, CK.,III, Clare-Salzler, M.J., et al: Disparate
roles for TNF and Fas ligand in concanavalin A-induced hepatitis. J. of
Immunol. 160:4082-89,1998.
25.
Solorzano, C.C., Moldawer, L.L., Clare-Salzler, M., et al. Parmacokinetics,
immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy
bacteremic baboon. J Appl Physiol 84(4):1119-30, 1998.
26.
Fukuzuka, K., Rosenberg, J.J., Moldawer, L.L., Clare-Salzler, M., et al.
Caspase-3 dependent organ apoptosis early after burn injury. Annals
of Surgery 229(6):851-8; discussion 858-9, 1999.
27. Litherland,
S.A., Xie, T., Hutson, A.D., Wasserfall, C., Whittaker, D.S., She, J.X.,
Hoffig, A., Dennis, M.A.,
Fuller, K.,
Cook, R., Schatz, D., Moldawer, L.L., Clare-Salzler, M.J. Aberrant
Monocyte prostaglandin Synthase 2 Expression Defines and Antigen Presenting
Cell Defect and is a Novel Cellular Marker for Insulin Dependent Diabetes
Mellitus (IDDM). J. Clin. Invest. 104:515-523, 1999.
28. Clare-Salzler,
M. The immunopathogenic roles of anitgen presenting cell in the NOD mouse.
In: NOD mice and
related strains:
research applications in diabetes, AICS cancer, and other diseases.
(eds. Leiter, E.H., and Atkinson, M.A. pp101-120, 1998. (Landes Biosceince
Publishers, Austin, TX.).
29. D. S.
Whittaker, Bahjat, K.S., Moldawer, L.L., Clare-Salzler, M.J. Cyclooxygenase-2
mediated prostanoid
production
regulates human monocyte derived dendritic cell maturation and IL-12 production.
J. Immunol. (submitted).
Grant Support
Name of Individual:
Michael Clare-Salzler
Active/Pending
Active
Project Number
(Principal Investigator): 1PO1 A142288-0 (PI;Atkinson, Project II PI;Clare-Salzler)
Source: NIH/NIDDK/NIAI
Title of
Project (and/or Subproject): Immune Function in High and Low Risk Genotypes
in IDD
Dates of
Approved/Proposed Project: 1997-02
Annual Direct
Costs / Percent Effort: $117,592.00 (20% effort)
The major
goals of this project are to determine the effect of PGS2 expression on
peripheral tolerance mechanisms, mainly activation induced cell death.
Overlap (summarized
for each individual): There is no overlap with the proposed projects
Active/Pending
Active
Project Number
(Principal Investigator): 1PO1 A142288-0 (PI;Atkinson, Core B Director;Clare-Salzler)
Source: NIH/NIDDK/NIAI
Title of
Project (and/or Subproject): Immune Function in High and Low Risk Genotypes
in IDD
Dates of
Approved/Proposed Project: 1997-02
Annual Direct
Costs / Percent Effort: $47,118.00 (5% effort)
The major
goals of this project are... The overall goal of this core is to provide
investigators in the program project with mice for experimentation and
to develop new congenic strains.
Overlap (summarized
for each individual): There is no overlap with the proposed projects
Active/Pending:
Active
Project Number
(Principal Investigator): R37 GM-40586-11 (PI;Moldawer, Co-I Clare-Salzler)
Source: NIH/NIGMS
Title of
Project (and/or Subproject): Cytokine Regulation in Sepsis and Inflammation
Dates of
Approved/Proposed Project: 1997-06
Annual Direct
Costs / Percent Effort: $201,360.00 (25% effort)
The major
goals of this project are... The overall goal of this award is to examine
proinflammatory cytokine, cytokine inhibitor and anti-inflammatory cytokine
regulation in sepsis, and bacterial infections.
Overlap (summarized
for each individual): There is no overlap with the proposed projects
Name of Individual:
Michael Clare-Salzler
Active/Pending
Active
Project Number
(Principal Investigator): 1RO1 AI139250-01 (PI;Atkinson, Co-I Clare-Salzler)
Source: NIH/NIDDK/NIAI
Title of
Project (and/or Subproject): Mechanism of Immunotherapy in IDD Prevention
Trials
Dates of
Approved/Proposed Project: 1996-01
Annual Direct
Costs / Percent Effort: $252,000.00 (5% effort)
The project
aims to identify mechanisms that underlie the prevention afforded by antigen
specific immunotherapies for IDDM.
Overlap (summarized
for each individual): There is no overlap with the proposed projects
Active/Pending
Active
Project Number
(Principal Investigator): Final budget pending from NICHD/JDFI (PI;She,
Co-I Clare-Salzler)
Source: NIH/NICHD/JDFI
Title of
Project (and/or Subproject): Neonatal Screening for IDDM
Dates of
Approved/Proposed Project: 1999-03
Annual Direct
Costs / Percent Effort: $450,000.00 (5% effort)
The major
goals of this project are to establish a general population genetic screening
program for newborns and infants to identify subjects at risk for the devilment
of IDDM.
Overlap (summarized
for each individual): There is no overlap with the proposed projects
Active/Pending:
Active
Project Number
(Principal Investigator): PI;Clare-Salzler
Source: Juvenile
Diabetes Foundation International
Title of
Project (and/or Subproject): The Role of Myeloid and Lymphoid Dendritic
Cells in the Immunopathogenesis of NOD Diabetes
Dates of
Approved/Proposed Project: 1999-01
Annual Direct
Costs / Percent Effort: $99,563.00
The major
goals of this project are to determine the lineage development and function
of myeloid and lymphoid dendritic cells in NOD mice and determine the contributions
of each lineage to autoimmunity and tolerance.
Overlap (summarized
for each individual): There is no overlap with the proposed projects
Name
of Individual: Michael Clare-Salzler
Active/Pending
Pending
Project Number
(Principal Investigator): PI; Moldawer, Co-I;Clare-Salzler
Source: NIH/NIGMS
Title of
Project (and/or Subproject): Genetic Determination of TNFa Mediated Liver
Apoptosis
Dates of
Approved/Proposed Project: pending
Annual Direct
Costs / Percent Effort: $211,027.00 (5% effort)
The major
goals of this project to identify genes which contribute to sensitivity
and resistance to TNF mediated liver injury using a quantitative trait
loci analysis.
Overlap (summarized
for each individual): There is no overlap with the proposed projects
Current laboratory Space
Location;
D11-50, D11-41
Area: 1440sq-ft.
laboratory space
135sq ft. culture room
PI and Graduate
Student Offices; 130sq ft.
Laboratory
Areas
Mouse dissection
Cell preparation
Flow cytometry
preparation mRNA preparation
Cell Culture
Room Western blotting and electrophoresis
Microscopy
Data base and data analysis
RT-PCR
Laboratory Procedures
Cell Culture
Development
of Cell Lines
Generation
of Dendritic Cells
Purification
of peripheral blood monocytes
Dendritic
cell isolation from mice
Flow cytometry
Purification
of islet beta cells by flow cytometry
Characterization
of dendritic cells lineage by flow cytometry
Detection
of apoptotic cells
Detection
of T populations and cytokine production
Detection
of PGS-2 positive monocytes
Protein Analysis
Western blotting
Protein purification
Immunoprecipitation
Electromobility
shift assays (EMSA)
Molecular
Biology
RT-PCR
DNA Sequencing
Cytokine
and Prostanoid ELISAs
PGE2, PGE1,
Thromboxane, PGD2,
IL-12, IL-10,
IL-6, IL-4, IL-2, IL-1, TNF
Microscopy
Plain light
and fluorescent
Equipment
Cell Culture
Hoods (3)
Dark Room
Cell culture
cabinets (2)
Densitometer
Centrifuges
(2)
Scintillation
Counter
Microfuges
ELISA plate
reader
Electrophoresis
equipment
Mouse colony
Gel boxes
Flow cytometer
Thermocycler
ELISA Plate
washer
Cytospin
Fluorometer
Hematology
analyzer
Cryostat
Magnetic
cell isolation equipment
Hybridization
oven
Phase contrast
microscope
Two computers
for data storage, analysis
Fluorescent
microscope
Freezers
(3)
Refrigerator
(3)