# RAGE, DIAPH1 and IRF7 and Macrophage Dysfunction in Atherosclerosis and Cardiometabolic Disease > **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $501,779 ## Abstract Summary: Project 3 Our Program Project has unveiled key roles for macrophage metabolism, depot-, cue-, and time-dependent molecular re-programming and intraorgan trafficking in the pathogenesis of cardiometabolic dysfunction. In each metabolic setting, including the atherosclerotic plaque, obese adipose tissue and liver, the composition of the tissue-specific niche, such as excess lipid content, and recruitment and trafficking of infiltrating bone marrow- derived immune cells, which deliver signals to activate endogenous signaling pathways in resident immune cells (e.g., adipose tissue macrophages or liver Kupffer cells), defines the breadth of possible consequences. Project 3 studies reveal novel, complex roles for the receptor for advanced glycation end products (RAGE; gene name Ager) and its cytoplasmic domain binding partner, DIAPH1, in parenchymal vs. immune cell dysfunctions. Project 3 key discoveries during Cycle 1 of the Program Project include: (1) deletion of Ager or Diaph1 in myeloid cells significantly increases insulin resistance without further increasing body mass in high fat diet-fed mice; (2) RAGE/DIAPH1 contributes to regulation of hepatic lipid metabolism; (3) macrophage RAGE contributes to regulation of Interferon Regulatory Factor 7 (IRF7); IRF7 bridges lipid metabolism and inflammation in macrophages; and (4) in mice fed a non-alcoholic steatohepatitis (NASH)-inducing diet, myeloid deletion of Ager or novel small molecule antagonists of RAGE/DIAPH1 imparts complex consequences on steatosis and fibrosis. These considerations lead us to hypothesize that RAGE/DIAPH1 contributes to regulation of macrophage metabolism; molecular re-programming in response to tissue- and cue-specific stimuli; and macrophage intra- and interorgan communications in cardiometabolic dysfunction. We will pursue three specific aims: Aim 1 will test the hypothesis that DIAPH1 contributes to atherosclerosis through intra- and interorgan regulation of lipid metabolism and inflammation; AIM 2 test the hypothesis that RAGE/DIAPH1/IRF7 uncouples liver steatosis and fibrosis in NASH through regulation of lipid metabolism and dynamic reprogramming of infiltrating Mɸs and resident Kupffer cells; and AIM 3 will test the hypothesis that RAGE/DIAPH1 contributes to cardiometabolic disease through interorgan communications. Project 3, with Projects 1-2, will identify the depot-, cue- and temporal-mediating mechanisms of cardiometabolic dysfunction, driven by macrophages and, critically, their interactions with parenchymal and non-parenchymal niche-specific cells. Fortified by complementary examinations in human tissues and transcriptome databases, we will employ state-of-the-art RNA sequencing, coupled with strategically-utilized spatial transcriptomics, to generate and “visualize” a comprehensive map of the putative interactome and the upstream transcriptional regulators that regulate intra- and interorgan cross- talk in cardiometabolic disorders. This work and the ... ## Key facts - **NIH application ID:** 10424906 - **Project number:** 2P01HL131481-06 - **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE - **Principal Investigator:** ANN MARIE SCHMIDT - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $501,779 - **Award type:** 2 - **Project period:** 2017-05-01 → 2027-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10424906 ## Citation > US National Institutes of Health, RePORTER application 10424906, RAGE, DIAPH1 and IRF7 and Macrophage Dysfunction in Atherosclerosis and Cardiometabolic Disease (2P01HL131481-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10424906. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*