Marcia F. McInerney, PhD.
Marcia F. McInerney, PhD, Distinguished University Professor and Chair of the Medicinal and Biological Chemistry in the College of Pharmacy and Pharmaceutical Sciences
Dr. McInerney received her PhD from the University of Michigan. Before she joined
the University of Toledo College of Pharmacy in 1991, she was a Postdoctoral Fellow
in Immunobiology in the laboraotry of Dr Charles Janeway at Yale University School
of Medicine in New Haven, Connecticut. Dr. McInerney has also been a Visiting Professor
of Medicine at Harvard (1998-1999) and is an Adjunct Professor of Internal Medicine
at the University of Michigan in the Division of Diabetes, Metabolism and Endocrinology.
Dr. McInerney major research interest is in elucidating the underlying immunopathological mechanisms in diabetes with the hope that a better understanding of the molecular and cellular basis for the disease will lead to better diagnostic, preventative and therapeutic strategies.
A major focus of her research is on the autoimmune aspects of Type 1 or insulin-dependent diabetes, using the nonobese diabetic (NOD) mouse as a primary model. In humans and the NOD mouse, insulin-dependent diabetes is inherited. Autoantibodies to insulin and islet cells are produced, and T lymphocytes invade the islets in the pancreas. T-cell invasion or insulitis is associated with destruction of the insulin-secreting beta cells. In the NOD mouse, insulitis begins at 4-6 weeks of age, however the mice do not spontaneously become diabetic until 3 to 6 months of age, at which time sufficient beta cells have been destroyed to result in the loss of insulin secretion. Other investigators have shown that the insulin receptor (IR) can function as a chemotactic receptor capable of directing cell movement in response to a gradient of insulin. Published data from my laboratory has shown that flow cytometry sorted T lymphocytes, from diabetic NOD mice, expressing a high density of insulin receptors (IR+ T cells) aggressively transfer insulitis and diabetes while T cells with low to negative IR expression (IR- T cells) are capable of neither. An association of IR+ T cells with an increased risk for diabetes would provide a new target for drug therapy. Furthermore, chemotactic signaling and metabolic signaling are mediated by distinct parts of the insulin receptor and could therefore, be selectively targeted for therapeutic intervention prior to diabetes onset. Current research in her laboratory involves the development of flag tagged, T cell specific, IR transgenic mouse on a background that does not spontaneously become diabetic to determine if movement of T cells into an islet can be based on IR expression. They have been successful in two of the transgenic models and now wish to make a transgenic mouse that has IR expression on the surface of Tregs to prevent the development of type 1 diabetes. We will be using Cre-Lox transgenic mice systems to reach this goal. There are areas of translational research associated with this work on high density IR expression using peripheral blood from human diabetic patients. The recent NIH/NIDDK grant (2014-18) supports this research.
A prime interest of her laboratory is in identifying dietary and genetic risk factors in Obesity and Insulin Resistant or Type 2 Diabetes. The work on obesity and type 2 diabetes was a collaborative USDA-funded research project for 6 years with Dr. Sonia Najjar, who was at the time at The University of Toledo, College of Medicine. Type 2 Diabetes is a complex disease usually involving abnormal metabolism resulting from both genetic predisposition and environmental factors. Diet and lack of exercise play critical roles in obesity, which may progress to diabetes and its complications. By identifying dietary and other environmental factors that act upon genetic predisposition, strategies may be developed and implemented to prevent obesity, diabetes and its associated diseases. As of November, 2005, 20.8 million Americans have diabetes and the cost to society has increased to $150 billion a year making the impact of diabetes highly significant in the United States. Recently, the American Diabetes Association indicated that of the live births in 2000, 1 out of every 3 will be diabetic in their lifetime and for minorities this is 1 in 2. These are horrendous statistics making the work on diabetes highly significant. The USDA work has resulted in numerous publications and meeting presentations/seminars.
Another major basic science focus involves assessment of innate immune responses to oral pathogens in diabetes. Diabetes is a risk factor for severe periodontal disease caused by gram negative anaerobes. Previous studies suggest that both innate and adaptive immunity are involved in protection against periodontal infection. Innate immune responses are the first line of defense against infection. Innate immune system cells, such as macrophages, react to common microbial surface molecules through newly discovered receptors on the macrophage cell surface called Toll-like receptors (TLRs). Our purpose is to determine the role of TLRs in the initiation of host immune responses against oral pathogens in periodontal infection, using the nonobese diabetic (NOD) mouse model of type 1 diabetes as well as animal models for type 2 diabetes. Macrophages respond to live bacteria and/or lipolysaccharide (LPS), derived from gram negative bacteria,by producing cytokines, expressing costimulatory molecule(s), fluctuating the TLR mRNA and protein levels and promoting TLR signal transduction. These events are essential for macrophage activation and initiation of specific adaptive immune responses for the generation of antigen specific cells. Macrophage activation in response to bacteria or LPS from oral pathogens will be compared in diabetic and nondiabetic mice. The working hypothesis is that a defect in innate immunity in diabetes contributes to the susceptibility to periodontal infection since it is likely that the interaction between the TLR and the oral pathogen initiates immune responses.
Innate immunity was also the focus of her 2008 sabbatical at the University of Michigan in the Department of Internal Medicine, the Division of Metabolism, Endocrinology and Diabetes. Two review papers on innate immunity and diabetes were generated associated with this sabbatical.
Work continues with collaborators Drs Quinn, Wall, and Sucheck on bioconjugates for delivery to present altered peptide ligands to prevent diabetes development in animal models.
Dr. McInerney has received research funding from the American Diabetes Association
(CAREER Development Award), the Juvenile Diabetes Research Foundation, Diabetes Action
Research and Education Foundation, and NIH and is currently supported by NIFA/USDA.
Dr McInerney is a committee member for NIDDK grant review.
Dr. McInerney has authored 30 peer-reviewed articles.