Project Summary and Abstract (Description) The major theme of the proposed research centers on how obesity contributes to the proliferation and differentiation of dendritic cell (DC)-restricted common DC progenitor cells (CDPs) for developing airway inflammation. The hypothesis is based on that obesity exacerbates airway inflammation in asthma by inducing the proliferation and differentiation of CDPs in the BM, which enhances the ability of DCs in the lung to promote adaptive immune responses. A specific objective of the research in the proposal is to identify novel endogenous signaling pathways and druggable targets in CDPs related to adaptive immunity that regulates airway inflammation in obesity. The proposal will utilize synergistic combination of murine models of experimental obesity- induced airway inflammation and cellular investigations of immune and progenitor cell functions. The first Aim will employ the very low density lipoprotein receptor (VLDLr) knock-out (VLDLr- /-) mice to determine the role in CDP proliferation and differentiation. In particular, the influence of VLDLr in cell cycle regulation and CDP proliferation will be evaluated. The hypothesis that VLDLr negatively regulates proliferation and differentiation of CDPs can be quantitatively tested by bone marrow transfer (BMT) experiments using VLDLr-/- mice. Understanding the role of VLDLr in DC- restricted progenitor cells will be essential for studying myelopoiesis in diet-induced obesity. The second aim develops the therapeutic strategy that includes targeting the VLDLr with an apolipoprotein E (apoE)-mimetic peptide to block CDP proliferation and differentiation. VLDLr are receptor for apoE and targeting progenitor cells with an apoE mimetic peptide will be suggestive of a druggable target for blocking the pathways of myelopoiesis in obesity. The third aim uses novel signaling pathways on DC-restricted progenitor cell differentiation during obesity associated airway inflammation (OAI). The hypothesis that obesity promotes p38 MAPK signaling pathways and regulates DC differentiation and airway inflammation can be quantitatively tested using p38 mutant mice that specifically show attenuated p38 MAPK signaling. Establishing the substrates and transcription factors of p38 MAPK signaling will be crucial for DC differentiation in OAI. The candidate is currently a research fellow at NHLBI in the Laboratory of Asthma and Lung Inflammation. The proposal describes a combined research and training program leading to independence. During the mentored phase of this project the candidate will continue training in BMT, flow cytometry and stem/progenitor cell assay techniques, as well as develop other skills necessary for a successful academic career. A list of leaders in the fields of asthma and lung inflammation, lipoprotein signaling, stem and progenitor cell proliferation, flow cytometry working at the NIH have agreed to provide this training through frequent lab visits that inclu...