A number of Internal Medicine members have received favorable responses to VA Merit Award applications. We would like to congratulate four of those researchers, who describe the work these grants will fund below.
Lee-Ann Allen, PhD
Professor of Internal Medicine – Infectious Diseases
Professor of Microbiology and Immunology
Dysregulation of the inflammatory response by Francisella tularensis
$924,384 over 4 years
Tularemia is a potentially fatal disease caused by the intracellular bacterium, Francisella tularensis. This competitive renewal award funds innovative studies to examine metabolic reprogramming of human neutrophils as a new aspect of tularemia pathogenesis and a previously unappreciated mechanism for manipulation of neutrophil lifespan during infection. The specific roles of bacterial lipoproteins and a polymorphism in human TLR1 in these processes will also be examined and potential points for therapeutic intervention will be identified.
Frank Faraci, PhD
Professor of Internal Medicine – Cardiovascular Medicine
Professor of Pharmacology
Impact of the central RAS on the brain microcirculation
$650,000 over 4 years
This grant focuses on the impact of the brain renin-angiotensin system (RAS) on small vessel disease (SVD), a key cause of strokes and a major contributor to cognitive deficits, dementias, and other neurological diseases. Our goal is to define mechanisms by which the cerebral circulation is affected by the local brain RAS. We focus on the microcirculation. Our knowledge regarding this segment of the vasculature is inversely related to its clinical importance. Currently there are no specific therapies for SVD.
Stephen McGowan, MD
Professor of Internal Medicine – Pulmonary, Critical Care and Occupational Medicine
Guidance of pulmonary fibroblast migration during alveolar septal formation
$650,000 over 4 years
We will study mechanisms guiding pulmonary alveolar septal fibroblast migration as they apply to alveolar generation. We focus on elements of the intracellular cytoskeleton and how they are linked to tensile proteins in the extracellular matrix. We will examine how platelet-derived growth factor-alpha, neuropilin-1, and discoidin domain receptor-2 contribute to lamellipodia formation and remodeling of focal adhesions and subjacent collagen fibers during migration.
William Nauseef, MD
Professor of Internal Medicine – Infectious Diseases
Professor of Microbiology and Immunology
Determinants of human neutrophil fate after phagocytosis
$600,000 over 4 years
The work proposes studies using Staphylococcus aureus and Neisseria gonorrhoeae as tools to interrogate signaling pathways that control neutrophil survival and cell death. There are two aims: (1) to determine the mechanisms that regulate human PMN fate and (2) to determine the mechanisms underlying hPMN secretion of IL-1b during phagocytosis.
We will elucidate fundamental aspects of human neutrophil biology that figure prominently in the resolution of the human inflammatory response. An effective immune system must both respond to threats and also restore tissue homeostasis. Despite critical links between innate immune cell fate and the timely resolution of inflammation, the crosstalk in molecular signaling among the pathways towards survival, apoptosis, and necrotic cell death is complex and incompletely understood. Activated human PMN and their secreted products sculpt the inflammatory tone in tissue, and failure of human PMN to undergo apoptotic cell death derails the resolution phase of the inflammatory response and instead amplifies disease. We reason that elucidation of the biochemical determinants that dictate human PMN fate after phagocytosis will provide fundamental insights into the mechanisms driving them towards survival vs programmed cell death pathways. Findings from our proposed work will illuminate fundamental aspects of inflammation, with special focus on phagocytosis-induced human PMN death pathways and IL-1b secretion. From this perspective, understanding mechanisms for resolution of inflammation and restoration of homeostasis will provide a framework to inspire novel therapeutic interventions in a wide range of clinical settings.