Investigating the Ferrostatic Role of Adipose Tissue Macrophages - PROJECT SUMMARY Iron is a micronutrient that is essential for nearly every living organism, and maintaining its homeostasis therefore represents a crucial biological problem across all scales: from cells, to tissues, to the whole organism. We propose that central regulation of local iron supply in the adipose tissue is controlled by VAMs (vasculature- associated macrophages), which are resident tissue macrophages that associate closely with the vasculature and perform several key homeostatic maintenance functions within the tissue. While VAMs and other tissue macrophages have been historically linked to host defense/innate immunity, there is a major gap in our understanding of their diverse functions beyond immunity, and how their dysfunction drives the progression of chronic inflammatory diseases such as type 2 diabetes. Gene expression profiling indicated that VAMs express an array of genes involved in iron handling, including iron import, export, processing, and storage. Our preliminary data shows that VAMs take up significant amounts of transferrin - the main iron carrier in blood serum - and also serve as an iron storage depot by housing significant amounts of intracellular iron. Together, we hypothesize that VAMs are the main regulator of white adipose tissue iron content, constantly monitoring the demand and controlling the local supply of iron to other cells. This study aims to elucidate the tissue-level iron handling functions of VAMs by 1) Identifying the primary iron uptake pathway in VAMs. 2) Ascertaining the role of VAM-mediated iron export and storage in regulation of adipose tissue iron content and systemic metabolism. 3) Uncovering the molecular mechanisms for adaptation of adipose tissue cells to perturbations in local iron availability. To answer these questions, we developed novel mouse models that target tissue-resident macrophages with very high specificity, thus overcoming a major barrier that currently exists in the myeloid field. This study will advance our understanding of the multifaceted roles of our immune system beyond immunity, with a focus on achieving deep mechanistic understanding of macrophage-mediated support of tissue physiology and specifically of tissue-level iron homeostasis. It may inform the biology of several diseases characterized by iron dysregulation, including type 2 diabetes, hematological and neurological disorders, and cancer. The results of this work may influence the development of treatments aimed to restore the proper cellular functions of dysregulated resident macrophages. This is a dissertation project which will be conducted in the lab of Dr. Hernandez Moura Silva at the Ragon Institute of Mass General, MIT, and Harvard, which has all the necessary facilities to perform the experiments described and provides an excellent training environment for the investigation that spans across the fields of immunology, physiology, and biochemistry. The proposed training plan will strengthen the candidate’s preparation to a career in research & development in an industrial sector, where interdisciplinary skills are essential.
