Please join us in congratulating Drs. Andrew Bryant and Divya Patel on their recent grant funding announcements. Dr. Andrew Bryant was recently announced as a recipient of an NIH R01 and Pulmonary Hypertension Accelerated Bayer Award. Dr. Divya Patel was recently announced as a CHEST foundation research grant on sarcoidosis. Please see the summary of their proposed research below:
Dr. Bryant R01 award: Project Title: Role of CXCR2-mediated cell trafficking in pulmonary vascular remodeling
In this project, our laboratory will be examining the role of chemokine receptor CXCR2 in the recruitment of a specific myeloid cell (myeloid-derived suppressor cells; MDSC) to the lung. Subsequently, we will examine the development of vascular remodeling resulting in pulmonary hypertension, associated with accumulation of these cells. While MDSC are known to play an integral role in the progression of many malignancies, it is unknown how these immune tolerizing cells traffic to, and activate within, the lung. The central hypothesis of this grant is that tissue specific, vascular endothelial versus myeloid cell, CXCR2 expression is necessary for recruitment of a specific sub-population of MDSC to the pulmonary vasculature. The rationale for the proposed research is that, upon completion of experiments, future studies can be proposed taking advantage of University of Florida expertise in tissue-specific delivery of either existing CXCR2 inhibitors though use of nanoparticle technology, or CXCR2 directed gene-therapy utilizing viral vectors. The contribution of these studies will thus be significant because it represents a strategy to improve clinical outcomes through prevention of CXCR2-mediated trafficking to the lung. Additionally, the proposed research is innovative because it represents a departure from the status quo by shifting focus from vasodilator therapy to an immunoregulatory mediator, MDSC, in the pathobiology of PH.
Dr. Bryant PHAB award : Our group has recently described how a specific bone-marrow derived (or myeloid-derived) cell contributes to pulmonary hypertension in patients with disease. This relationship appears to be mediated in part through a specific immune checkpoint signaling axis – programmed cell death protein 1 (PD-1) and the corresponding programmed death-ligand 1 (PD-L1) – involved in the recruitment and activation of these myeloid-derived cells. Sleep fragmentation is known to increase the amount of PD-L1 on myeloid cells in the peripheral blood of healthy people. However, it is unknown how changes in cellular circadian patterns influence recruitment of PD-L1 expressing myeloid cells to the lung, contributing to pulmonary hypertension. Moreover, it is undetermined how changes induced by oscillatory disturbances impact changes in myeloid cell circadian rhythm resulting in augmented trafficking of these cells to the lung. This proposal aims to fill these gaps in knowledge, first by addressing the role of circadian biologic rhythms in pathologic activation of this cell population to the lung, contributing to development of pulmonary hypertension. Second, we will directly manipulate an essential protein involved in myeloid cell circadian rhythm, in our models of pulmonary hypertension, in order to assess target suitability for application of existing drugs to patients with pulmonary hypertension. Thus, our hope is that these studies will lead to the translation of existing clinical therapies directed at lung vascular disease; a large patient population without any current disease-specific curative therapy. Broadly, it is therefore expected that results from proposed studies will be a step in the right direction for limiting both mortality and health-care cost utilization by patients with pulmonary hypertension.
Dr. Patel CHEST foundation award : Sarcoidosis is an inflammatory condition that can affect any organ but commonly affects the lungs. A problem in treatment of sarcoidosis relates to the use of methotrexate, a commonly prescribed medication in this disease. The use of methotrexate is complicated by a) only 40-60% of people improve with treatment; b) it takes 3-6 months to work; and c) there are many side effects that may require discontinuation of the drug. One reason for these complications may be genetic variation between people which impacts how the drug is metabolized by the body. One solution to this problem is identifying patients who will or will not respond to the methotrexate before starting the treatment. In our study we would like to look for genetic variations amongst people who did and did not respond to methotrexate and between those that did and did not have side effects. These genetic variations have already been studied in another disease, rheumatoid arthritis, in which methotrexate is also used for treatment. If we can find differences between the groups that respond to treatment and those that do not, this could greatly benefit sarcoidosis patients in the future by shortening the time between diagnosis and getting started on medication that is effective.”