In the initial funding period of this award we provided conclusive evidence that dendritic cells play a central role in the pathogenesis of periodontal disease and that this function is modulated through FOXO1 and Akt1. Contrary to our expectations, lineage specific FOXO1 deletion in dendritic cells significantly increased susceptibility to periodontitis whereas the opposite result occurred when Akt1 was deleted in dendritic cells. DC-specific Akt1 deletion blocked bacteria-induced periodontitis whereas DC-specific FOXO1 deletion increased it. These exciting results provide the first concrete evidence that DC play an instrumental role in modulating susceptibility to periodontitis and suggest a mechanism through Akt1 and FOXO1. Dendritic cells have multiple functions that can affect periodontal inflammation and bone loss. They may produce factors that may favor the formation of T regs, which have been shown to reduce periodontal breakdown. They also can direct the production of an antibody response that is potentially protective. Alternatively, DCs can transdifferentiate to osteoclasts, effector cells responsible for bone resorption. We will examine each of these three potential mechanisms through which the FOXO1 and Akt1 May regulate DC to control susceptibility to periodontitis. We propose three mechanisms by which FOXO1/Akt1 can modulate susceptibility to periodontitis. These mechanisms are compatible with each other and all three could potentially play a role. The experiments involve an in vivo experimental model of P gingivalis and F nucleatum induced periodontitis in mice with lineage specific FOXO1 or Akt1 deletion in DC along with companion in vitro studies. The goal of Aim 1 is to establish mechanisms through which FOXO1 in dendritic cells modulates periodontal disease susceptibility, while the goal of Aim 2 is to establish mechanisms through which Akt1 has the opposite effect. Three compatible mechanisms will be investigated, modulation of the adaptive immune response by altering Treg/Th2 versus Th1/Th17 responses, alteration of an antibody response that confers protection against periodontal breakdown, and transdifferentiation of immature DC to osteoclasts.

Public Health Relevance

We have demonstrated the dendritic cells regulate susceptibility and resistance to bacteria induced periodontitis that is mediated by Akt1 and FOXO1. We propose three compatible mechanisms through which this may occur and will investigate each with lineage specific deletion of Akt1 or FOXO1 driven by CD11c-Cre recombinase.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE021921-07
Application #
9657744
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Chander, Preethi
Project Start
2012-06-01
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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