This application details a five-year career development program to facilitate the transition from a mentored post-doctoral fellow to an independent researcher. The applicant has completed 4.5 years of post- doctoral training, 1 in the UK and 3.5 at the University of California, Los Angeles. The applicant will continue to be mentored by Dr Peter Edwards, a recognized leader in the field of cholesterol and lipid metabolism. Dr Peter Tontonoz, a highly respected scientist with expertise in the areas of nuclear receptors, inflammation and cardiovascular disease, will act as co-mentor to the applicant. Importantly, Drs Edwards and Tontonoz have successfully trained a number of investigators who have become independent academic scientists. Continued active interactions with Drs Kenneth Dorshkind (UCLA) and Joe Witztum (UCSD), both experts in B-1 B cells and natural antibodies (NAbs), adds particular strengths to specific aspects of the application. Inflammation is a hallmark characteristic of diseases such as atherosclerosis, autoimmunity, obesity and cancer. Inflammation is a stereotypical response of the innate (inborn) immune system to pathogens. Factors that influence inflammation can have a profound effect on disease progression. For example, the formation of fatty streaks and subsequent progression to atherosclerotic lesions is associated with accumulation of cholesterol and cholesterol esters within the intima of the artery wall. These changes in intracellular and extracellular lipids resul in an inflammatory response that is generally thought to have deleterious effects on lesion development. I am particularly interested in identifying proteins that affect lipid deposition, inflammation and disease, and then defining their mechanism of action. To this end, we have shown that i) the ATP Binding Cassette Transporter G1 (ABCG1) modulates both intracellular sterol movement and facilitates the transport of cellular cholesterol and oxysterols to exogenous lipid acceptors and ii) mice lacking ABCG1 develop severe pulmonary lipidosis and chronic inflammation. Unexpectedly, Abcg1-/- mice exhibit reduced atherosclerosis, despite enhanced levels of pro-inflammatory cytokines and increased pulmonary lipid deposition. The primary aim of this proposal is to understand the mechanisms involved in maintaining inflammatory responses and the role of ABCG1 in lipid homeostasis, inflammation, and innate immunity.
In Specific Aim 1 I will test the hypothesis that cell-specific deletion of ABCG1 has significant consequences for inflammatory responses. I propose to generate mice deficient in ABCG1 specifically in type II pneumocytes (T2 cells;Abcg1T2-/T2-). I will then study the Abcg1T2-/T2- mie to determine the specific importance of T2 cell ABCG1 on surfactant metabolism, lung lipid homeostasis, including the effect on the generation of lipid antigens that affect innate immunity and inflammation.
In Specific Aim 2 I will test the hypothesis that loss of ABCG1 modulates innate immunity, inflammation and atherosclerosis progression. Using adoptive transfer studies and Rag2-/-Ldlr-/- hyperlipidemic mice, I will then determine the relative contribution of differen B cell subtypes that lack ABCG1 on the development of atherosclerosis, focusing particularly on the athero- protective function of B-1 B cells and secreted NAbs. One of the long term goals of the studies put forward in this application is to further understand factors that mediate inflammatory responses and how they translate to disease prevention, using the innate immune system and atherosclerosis as model systems.
Atherosclerosis is a multifactorial disease that integrates dysregulated lipid homeostasis and inflammatory responses. Understanding the complex biology and signals that occur at a molecular level and how that translates into the clinical manifestation of the disease, will facilitate the identification of additional targets for the intervention of inflammatory and metabolic diseases.
|Tarling, Elizabeth J; Edwards, Peter A (2016) Intracellular Localization of Endogenous Mouse ABCG1 Is Mimicked by Both ABCG1-L550 and ABCG1-P550-Brief Report. Arterioscler Thromb Vasc Biol 36:1323-7|
|de Aguiar Vallim, Thomas Q; Tarling, Elizabeth J; Ahn, Hannah et al. (2015) MAFG is a transcriptional repressor of bile acid synthesis and metabolism. Cell Metab 21:298-310|
|Wei, Hao; Tarling, Elizabeth J; McMillen, Timothy S et al. (2015) ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction. J Lipid Res 56:2337-47|
|Tarling, Elizabeth J; Ahn, Hannah; de Aguiar Vallim, Thomas Q (2015) The nuclear receptor FXR uncouples the actions of miR-33 from SREBP-2. Arterioscler Thromb Vasc Biol 35:787-95|
|Ito, Ayaka; Hong, Cynthia; Rong, Xin et al. (2015) LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. Elife 4:e08009|
|Baldan, Angel; Gonen, Ayelet; Choung, Christina et al. (2014) ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis. J Immunol 193:5637-48|