Pathophysiology

Inflammation

A major focus of the lab is understanding how inflammation contributes to human pathophysiology, as we search for myeloid targets to treat major diseases. Our research centers around two myeloid compartments: macrophages and dendritic cells. 

Macrophages are a key cellular compartment and represent nearly 50% of immune cell mass. By constantly sensing and responding to threats, macrophages play vital roles in maintaining organismal homeostasis and repairing tissue injuries. It is well established that macrophages accumulate in human lesions, correlating significantly with many clinical disease outcomes. More than a decade ago, we discovered that macrophages arise from two distinct origins, the tissue resident macrophages (RTMs) and monocyte-derived macrophages (mo-macs). In steady state conditions, RTMs can self-renew, maintain organ homeostasis by clearing damaged cells, promote vascular and neuronal integrity, and control energy expenditure. During diseased states, circulating monocytes are recruited into tissues, where they differentiate into pro-inflammatory mo-macs that are fundamentally distinct from RTMs. Our lab seeks to understand the functional specialization and contribution of RTMs and mo-macs, identifying novel macrophage drivers of disease. 

While fewer in number compared to macrophages, dendritic cells (DCs) are extremely potent antigen presenting cells embedded throughout all tissues. DCs have extraordinarily broad abilities: sense damage, capture cell-associated antigens, migrate to tissue-draining lymph nodes, and instruct T cell differentiation programs. Therefore, DCs are uniquely equipped to prime T cell responses against foreign antigens and induce regulatory; T cells tolerance to self-antigens, making them important targets for the treatment of inflammatory diseases. ;

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Cancer

Over the last decade, our lab has concentrated on high-dimensional profiling of inflammatory components of human cancers, and how immunotherapy agents can modulate disease pathogenesis. 

In close collaboration with Mount Sinai surgeons, pathologists, and interventional radiologists, we have built an efficient cutting-edge tissue pipeline to collect patient samples across many longitudinal timepoints and combination immunotherapy treatments. We use cutting-edge technologies to map the molecular composition of lesions with single-cell and spatial resolution. This deep profiling is paired with multiplex measurements of the blood borne factors that control systemic inflammation and immunotherapy resistance using proteomic technologies.

By drawing insights from human samples, we generate hypotheses on drivers of disease that can be tested in the lab using reductionist models. See below for examples of how our comprehensive bench-to-bedside pipeline has transformed our understanding of anti-tumor immunity, with impacts not only in the local tissue environment but also systematically in the host. 

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Aging

By the year 2050, more than 25% of the world will be aged 60 years or over. Our laboratory seeks to understand why age is one of the largest risk factors for myeloid-driven inflammatory diseases, and uncover new pathways which specifically promote disease in elderly patients. With the extensive knowledge, pipelines, and models our laboratory has developed so far, we are investigating how aging tissues can enhance well-known inflammatory drivers. Please reach out to learn more about our ongoing research projects which explore the intersection of aging and transposable elements, GLP-1 agonists, diet, and other incredibly diverse topics. 

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