tate the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Primary Biliary Cirrhosis (PBC) is a chronic inflammatory liver disease that usually progresses to liver failure and death unless liver transplantation is performed. Although the etiology of PBC is not well understood, both genetic and environmental factors are known to contribute. Recent clinical studies strongly suggest that infection with Novosphingobium aromaticivorans (N. aro) is specifically associated with development of PBC in predisposed individuals. Utilizing a mouse model, we have recently shown that N. aro infection of mice results in the development of PBC-like liver lesions, which are dependent upon the production of IFN-? and IL-17 through activation of NKT and conventional T cells. Based on our preliminary data that NOD mice expressing the B6 CD101 allele or mice deficient in CD101 expression exhibit more severe PBC than their congenic or wildtype littermates, we propose that the CD101 gene, which lies within the Idd10 diabetes locus, that encodes the expression of the negative co-stimulatory molecule is a novel PBC susceptibility gene. Thus the overall goal of this proposal is to determine the role of CD101 in susceptibility/resistance to severe PBC. Although the exact mechanisms by which CD101 susceptibility alleles regulate T cell activation and PBC are unknown, our preliminary findings support the hypothesis that diminished/altered signaling by the B6 CD101 allele on the NOD background mediates enhanced T cell signals through Vav3 activation and/or lack of PTPN22 induction that impair the balance between regulatory and effector T cells and leads to enhanced inflammation and liver disease. To test this hypothesis, we aim to: 1) further explore the role of CD101 in the acute and chronic phases of N. aro-induced PBC;2) determine whether genetic differences in CD101 increase DC-mediated activation of NKT and/or conventional T cells, and, thereby susceptibility to the chronic phase of disease;and 3) determine whether the differential regulation of T cell function in B6 CD101 congenic mice results from alterations in CD101-mediated regulation of Vav3 and/or PTPN22. Identification of CD101 as a susceptibility gene for PBC should provide valuable insight into the development of novel therapeutics to treat this life-threatening disease, but may also allow the identification of common targets in autoimmune disease for clinical intervention in the future. PERFORMANCE SITE(S) (organization, city, state) Children's Hospital Medical Center Cincinnati, OH KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Mattner, Jochen JOMATTNER CCHMC PI Wicker, Linda S. lwicker University of Cambridge Consultant Ridgway, William M. RIDGWAY2 University of Pittsburgh Consultant Gershwin, M. Eric MEGERSHWIN University of California at Davis Consultant Katz, Jonathan JDKATZ CCHMC Consultant Bezerra, Jorge BEZERRA CCHMC Consultant Bendelac, A. BENDELAC University of Chicago Consultant Hildeman, David DHILDE CCHMC Consultant University of Pittsburgh

Public Health Relevance

Environmental factors and genetic predisposition determine the susceptibility of an individual to autoimmune disease. In this regard, we have identified a single molecule, CD101 as risk factor for an uncurable human liver disease, Primary Biliary Cirrhosis in response to infection with an ubiquitous alphaproteobacterium. Using CD101 as readout system for different immune cell responses, this proposal will explore the cellular mechanisms by which the genetic background and bacterial infection influence the susceptibility of a mouse to chronic liver inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084054-05
Application #
8471694
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$248,273
Indirect Cost
$82,758
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Danzer, Claudia; Mattner, Jochen (2013) Impact of microbes on autoimmune diseases. Arch Immunol Ther Exp (Warsz) 61:175-86
Fusakio, Michael E; Mohammed, Javid P; Laumonnier, Yves et al. (2011) C5a regulates NKT and NK cell functions in sepsis. J Immunol 187:5805-12
Mohammed, Javid P; Fusakio, Michael E; Rainbow, Daniel B et al. (2011) Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. J Immunol 187:337-49
Rainbow, Daniel B; Moule, Carolyn; Fraser, Heather I et al. (2011) Evidence that Cd101 is an autoimmune diabetes gene in nonobese diabetic mice. J Immunol 187:325-36
Mohammed, Javid P; Mattner, Jochen (2009) Autoimmune disease triggered by infection with alphaproteobacteria. Expert Rev Clin Immunol 5:369-379