Glucocorticoids in short- and long-term critical illness outcomes

ABSTRACT Because of the high mortality, morbidity, and health care costs associated with critical illness, identifying biological mechanisms that can be targeted to improve critical illness outcomes is an important public health priority. Glucocorticoid treatment has been frequently studied in critically ill populations and can improve short-

term survival as well as long-term mental health outcomes. Full realization of the therapeutic potential of glucocorticoids in critical illness is hampered by gaps in our understanding of its mechanisms of action and by glucocorticoid resistance, which limits its efficacy. Our future research program will focus on the theme of

glucocorticoid mechanisms relevant to critical illness, with three main objectives. First, our prior work led us to hypothesize that glucocorticoids improve mental health outcomes by enhancing factual memories from the ICU. We will test this hypothesis in a population of sepsis survivors from our hospital. Second, we propose a novel

hypothesis about the importance of brainstem glucocorticoid signaling in the maintenance of cardiovascular and immune homeostasis. We will test the role of glucocorticoid receptors in this specific brainstem area in the response to acute hypotensive and inflammatory challenges using the tools and skills that we have acquired for

neural circuit interrogation. Finally, we propose to test a novel strategy to improve peripheral and central glucocorticoid sensitivity in collaboration with a new industry partner. Over the past five years I have positioned myself as a multidisciplinary leader across critical care, endocrinology, and neuroscience. My laboratory’s experience in running a translational research program at this

interface will lead to the identification of specific, targetable mechanisms to improve critical illness outcomes. Alongside these research goals, I will continue my work as a mentor for the next generation of scientists and physician-scientists. Because of the translational importance of our work and the inclusivity of our environment,

my lab has become a sought-after environment for scientific trainees. During this funding period I will continue to grow as a mentor and leader, cultivating a collaborative and diverse group that reflects and prepares the next generation of scientists.