Inflammatory bowel diseases (IBD) are multifactorial disorders that represent a significant public health challenge. Understanding the cellular and molecular mechanisms involved in the pathogenesis of IBD will be critical to the identification of predisposing factors and the design of novel, targeted therapeutics. Intestinal epithelial cells (IECs) have been strongly implicated in the pathogenesis of IBD. Although IECs provide an essential barrier and are crucial in regulating immune cells in the intestinal microenvironment, the underlying molecular mechanisms that regulate IEC function have not been elucidated. Consistent with a central role for epigenetic regulation in IBD, promising studies have identified histone deacetylase (HDAC) inhibitors as putative therapeutics for the treatment of intestinal inflammation, but the significance of HDACs in intestinal health and disease remains poorly understood. Studies outlined in this proposal will directly test the role of epigenetics in intestial homeostasis by defining the function of IEC-intrinsic HDAC3. Employing two newly developed mutant mouse strains and established murine models of intestinal inflammation, two specific aims of this project will determine (i) the influence of IEC-intrinsic HDAC3 expression on IEC homeostasis and mucosal barrier function and (ii) how IEC-intrinsic HDAC3 regulates the development and progression of intestinal inflammation and repair. Delineating the contribution of HDAC3 to IEC homeostasis and intestinal disease will significantly expand our understanding of the molecular mechanisms involved in IBD and could impact and justify the development of more selective HDAC inhibitors as therapeutics. During my training as a veterinary pathologist, I discovered my strong interest in epithelial regeneration, mucosal immunology and the pathogenesis of chronic intestinal inflammation. For this reason, I initiated the proposed project with Dr. David Artis that will build upon my knowledge of epigenetics and transcriptional regulation and enable me to transition into the field of mucosal immunology. My thesis work provided me with an excellent foundation in epigenetic regulation, but I have not had previous exposure to immunological techniques and intestinal disease models. The Artis lab and Penn offer an exceptional scientific and intellectual environment that will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. My understanding of disease pathology in a broad range of species, coupled with my experience in molecular biology and mouse model design and analysis, have provided me with a strong and unique foundation. Over the next five years, I fully anticipate this background in conjunction with my current research plan will allow me to successfully carry out the proposed project. The mentoring and training I will receive in Dr. Artis'laboratory and from the wider Penn community will enable me to successfully transition into an independent veterinary scientist that can address questions directed towards molecular advances in diagnostics as well as innovative and targeted therapeutics for intestinal diseases including IBD and cancer.

Public Health Relevance

Inflammatory bowel diseases (IBD) are complex disorders that represent a significant public health challenge. The goals of this proposal are to understand the influence of a molecule called HDAC3 in the development and function of intestinal cells. Delineating the influence of this molecule on the intestine will expand our understanding of the mechanisms that promote IBD and could impact the development of more effective drugs to treat IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK093784-01
Application #
8226148
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$154,235
Indirect Cost
$11,425
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Alenghat, Theresa (2015) Epigenomics and the microbiota. Toxicol Pathol 43:101-6
Alenghat, Theresa; Artis, David (2014) Epigenomic regulation of host-microbiota interactions. Trends Immunol 35:518-25
Alenghat, Theresa; Osborne, Lisa C; Saenz, Steven A et al. (2013) Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 504:153-7
Osborne, Lisa C; Joyce, Karen L; Alenghat, Theresa et al. (2013) Resistin-like molecule ýý promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation. J Immunol 190:2292-300