DESCRIPTION (provided by applicant): Macrophages (MØ) are among the immune system's most important defenders of the body by protecting against infection and injury but they also accelerate numerous diseases. Recent studies indicate that many tissue MØ are generated during embryonic development and maintain themselves in adults in the steady-state. In diseased tissues, however, many MØ originate from circulating monocytes (Mo). For example, we found that circulating Mo often infiltrate the ischemic myocardium, atherosclerotic plaques and growing tumors, where they differentiate into MØ and can promote disease. These circulating Mo can be released in large quantities from different reservoir locations, including th bone marrow and spleen, and various diseases enhance Mo production in these reservoirs by amplifying hematopoietic stem and progenitor cells (HSPC) locally. At present, an accurate understanding of disease-induced MØ responses is lacking and requires a more comprehensive analysis of the origins and dynamics of these cells at the organismal level. The research proposed in this application will define both the quantity and quality of tissue MØ based on thei origins. We propose that, in disease, distinct anatomical sites produce different types of MØ precursors and we will thus test the hypothesis that disease-associated tissue MØ responses can be tailored by manipulating these cells' topo-ontogenic sources. First, by taking the entire HSPC➝Mo➝MØ lineage into account we will identify the most important kinetic processes that define the quantity of disease-associated MØ (aim 1). Second, by considering the different origins of these MØ we will uncover maturational pathways that influence their quality in vivo (aim 2). Our findings have therapeutic potential because in both aims we will define how Ang II pathway manipulations control MØ. Ang II is a newly identified driver of HSPC/Mo/MØ-mediated inflammation that is active in a variety of diseases (cancer, atherosclerosis, myocardial infarction) and can be targeted with FDA-approved drugs. Our goal is to develop new advances that can be used to restrain unwanted inflammatory reactions or instead promote delivery of protective immunity to tissue. Our experiments will use the so-called KP tumor mouse model because we have generated data indicating that: i) MØ in KP tumors have a dominant phenotype and promote disease; ii) many of these MØ originate from HSPC and Mo that are produced in bone marrow and spleen; iii) HSPC➝Mo➝MØ lineage amplification in KP mice resembles the one observed in other disease models including myocardial infarction and atherosclerosis; and iv) the hormone Angiotensin (Ang) II amplifies disease-promoting MØ in KP mice. Also, we have assembled a team of experts in imaging, leukocyte trafficking, data modeling and integrative biology to accomplish our goals.