Immunosenescence of primary lymphatic organs is characterized by a decrease in the self-renewing potential of precursor cells as well as generation of lineage-committed cells affected by age-related changes. The consequences of immune decline are increased susceptibility to infections and cancer, and reduced responses to vaccinations. We recently reported, in collaboration with P1 and P3 of this Program Project (PP), that a hallmark of aging CD34+ bone marrow precursor cells as well as bona fide conventional dendritic cells (cDC) is the presence of an extensively glycated, carbonylated and lipoxidated proteome, which severely compromises their ability to mount effective immune responses. In this new PP period we propose to use a series of biochemical and biophysical approaches to: 1) functionally characterize the effects of different stressors on adaptive immune responses 2) analyze oxidative modifications of the cDC and M? immuno-proteome generated by these stressors 3) analyze the autophagic pathways involved in disposing the oxidatively modified proteome and 4) implement therapeutical intervention aimed at decreasing cellular stressors and restore adaptive immune functions. The overall working hypothesis of this project is that stressor-induced specific protein posttranslational modifications (carbonylation, glycation, lipoxidation) differently affect the cellular immuno-proteome, its autophagic clearance and ultimately the cDC, macrophages (M?) and CD4+ T cell immune functions.
In specific Aim 1 we will analyze the effects of cellular stressor on cDC and M? immunoproteome by using qualitative and quantitative mass spectrometry and free flow fractionation analysis of protein aggregates. The autophagic mechanisms use to dispose of the glycated, carbonylated and lipoxidated proteome will be evaluated using CD11c tissue specific null cells for the three autophagic pathways.
In specific Aim 2 we will analyze how different stressors, known to induce proteotoxicity and lipotoxicity compromise cDC-mediated adaptive immune responses.
In specific Aim 3 we will evaluate a series of genetic, pharmacologic and dietary therapeutic interventions shared with all projects to determine the best approach to decrease proteotoxicity and lipotoxicity on immune cells and restore adaptive immune functions Relevance: This application delves into previously unexplored areas of immunosenescence and immune cells response to stressors commonly encountered in diabetes, metabolic syndrome, prolonged infections and immune cell exhaustion. The overall fundamental goal is to understand the biochemical implication of each stressor on cDC and M? ability to mount adaptive immune responses and to devise therapeutic interventions aimed at restoring cellular functionality and improve immunosenescence.
The major long term goal of our study is to assess how the immune system responds to stress, including high fat diet, infections and protein damage. In particular we are interested in examining how immune responses and vaccine challenges are compromised by these stressor events and what are the strategies put in place by immune cells to counteract them. Our ultimate goal is to improve the overall efficiency of the immune response towards invading pathogens as well as the poor vaccine response normally associated with aging.
|Batista-Gonzalez, Ana; Singh, Rajat (2017) Lysosomal function in ?-cell survival during glucolipotoxicity. Ann Transl Med 5:471|
|Satori, Chad P; Ramezani, Marzieh; Koopmeiners, Joseph S et al. (2017) Checkpoints for Preliminary Identification of Small Molecules found Enriched in Autophagosomes and Activated Mast Cell Secretions Analyzed by Comparative UPLC/MSe. Anal Methods 9:46-54|
|Raz, Yotam; Guerrero-Ros, Ignacio; Maier, Andrea et al. (2017) Activation-Induced Autophagy Is Preserved in CD4+ T-Cells in Familial Longevity. J Gerontol A Biol Sci Med Sci 72:1201-1206|
|Martinez-Lopez, Nuria; Tarabra, Elena; Toledo, Miriam et al. (2017) System-wide Benefits of Intermeal Fasting by Autophagy. Cell Metab 26:856-871.e5|
|Maus, Mate; Cuk, Mario; Patel, Bindi et al. (2017) Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism. Cell Metab 25:698-712|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Martinez-Lopez, Nuria; Singh, Rajat (2016) Telemetric control of peripheral lipophagy by hypothalamic autophagy. Autophagy 12:1404-5|
|Martinez-Lopez, Nuria; Garcia-Macia, Marina; Sahu, Srabani et al. (2016) Autophagy in the CNS and Periphery Coordinate Lipophagy and Lipolysis in the Brown Adipose Tissue and Liver. Cell Metab 23:113-27|
|Champa, Devora; Orlacchio, Arturo; Patel, Bindi et al. (2016) Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis. Oncotarget 7:34453-71|
|Kaushik, Susmita; Cuervo, Ana Maria (2016) AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12:432-8|
Showing the most recent 10 out of 130 publications