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LUNG T32

Program Overview

Current Trainees

Training History

Program Eligibility

& Nominations

LinkedIn Group

Dr. Asrar B Malik


Program Director

Department of Pharmacology

Center for Lung and Vascular Biology

University of Illinois College of Medicine

835 S Wolcott Ave E403

Chicago, IL 60612


               Tel:          (312) 996-7635

               Fax:         (312) 996-1225

               E-mail:    abmalik@uic.edu

Shejuan An, MD

Advisor:  Asrar B Malik, PhD

(1st year supported in training program)

Title:  Epigenetic regulation of macrophage phenotype shift to M2

Abstract:  The aim of my research is to discover dynamic changes in chromatin accessibility in IL-4 treated macrophages and elucidate the mechanism of M2 macrophage regulating EC regeneration. The project is determining how IL-4 regulates the polarization to M2 macrophages and the specific transcription factors responsible for the shift. In these studies I will use mouse bone marrow precursor cells to differentiate into M2 macrophages by IL-4. The preliminary results showed that the PU.1, which drive the selection of a large fraction of macrophage-specific enhancers, was significantly increased in IL-4 induced M2 macrophages compared to M0 macrophages (control group). Other M2 markers such as CD206 and PPARgamma were also increased.  We will use the most sensitive high-throughput method ATAC-seq to identify the whole landscape changes of chromatin accessibility of the induced M2 macrophages, including nucleosome positioning, patterns of nucleosome-TF spacing, and footprints infer factor occupancy genome-wide. Based on the ATAC-seq results, we will select several top motif enrichment in newly open regions compared to other accessible regions to address the function of these region in the mechanism of the shift work in other studies.

Reyhaan Chaudhri, PhD

Advisor:  Jan Kitajewski, PhD

(1st year supported in training program)

Title:  Role of Jag1/Notch in Endothelial Interactions with Tumor Cells

Abstract:  Tumor angiogenesis and the interaction of tumor cells with endothelial barrier is crucial for entrance of tumor cells into circulation. Notch signaling regulates normal as well as pathological angiogenesis. We have developed Notch decoys that target specific Notch ligands, and have shown that Dll-specific Notch blockade increases sprouting angiogenesis; however, extended Dll4 inhibition results in toxic effects. We have shown that Jagged inhibition reduces sprouting angiogenesis without the toxic effects of Dll4 inhibition. In addition, the Jag/Notch signaling axis is implicated in the pathology of breast cancer cells, and high expression of Jagged is linked to poor outcomes. We hypothesize that Jag-specific Notch inhibition will reduce metastasis through effects on both tumor and endothelial cells by paracrine effects on sprouting angiogenesis and juxtacrine effects on endothelial barrier disruption.

Jeffrey Klomp, PhD

Advisor:  Jalees Rehman, MD

(2nd year supported in training program)

Title:  Mapping the transcriptional landscape of hypoxic endothelial cells

Abstract:  The blood, vasculature, and nervous systems are among the complex tissues that arise through the exquisite ability to respond to oxygen gradients during development. In disease, the return of oxygen to oxygen-deprived (hypoxic) tissues following loss of blood flow adds a major complication to heart and lung surgeries. In a similar manner, cells pre-conditioned with hypoxia are better able to respond to more severe hypoxic conditions later on. However, different cell types are not equally sensitive to oxygen levels nor do they exhibit the same responses. At the pinnacle of the body’s oxygen control are endothelial cells (ECs), the cells that line vessels. These cells are drivers of physiological homeostasis and mediators of inflammation as well as responsible for new vessel formation and consequently, changes in oxygen levels throughout the entire body. However, the activities of ECs at different oxygen levels are poorly understood. Therefore, our goal is to understand the molecular changes of ECs under hypoxic stress. By using new genomic, statistical, and computational methods, we can discern key biochemical changes that may lead to new therapeutic understanding. We have generated insights from preliminary work with non-ECs that justify an in-depth genome-level characterization of EC hypoxic response.

Andrew Stuart, PhD

Advisor:  Asrar Malik, PhD

(3rd year supported in training program)

Title:  Nanoparticle Interactions with Polymorphonuclear Leukocytes and Endothelial Cells

Abstract:  Endothelial cells form a tight and restrictive barrier between particles circulating in the vasculature and the epithelium and underlying tissue. In order to provide therapies to the underlying tissue, small molecule therapeutics need a delivery method that can provide proper dose, site specificity, and transport through the endothelium. One significant problem with a number of small molecule therapeutics is their low solubility in water and plasma. This problem can be solved by loading the small molecules into soluble nanoparticles, which can increase circulation and allow for cell specificity by decorating the exterior of the nanoparticles with functional group. We recently discovered that our novel albumin based nanoparticles were preferentially internalized by polymorphonuclear leukocytes that were adherent on the endothelium under TNF-alpha induced inflammation conditions. This discovery led to an important therapeutic application using the low solubility small molecule piceatannol, which was recently published in nature nanotechnology (DOI: 10.1038/NNANO.2014.17). We are currently evaluating this therapy in robust acute lung injury models, as well as using the newly discovered albumin nanoparticle targeting system to deliver a variety of other therapeutics to adherent neutrophils and endothelial cells.

Shiqin Xiong, PhD
Advisor:  Asrar Malik, PhD

(1st year supported in training program)

Title:  Endothelial Caspase-11-Mediated Pyroptosis in Acute Lung Injury

Abstract:  Endothelial pyroptosis exhibits a homeostatic role in host defense and immune surveillance of the vasculature.  We show that activation of endothelial Caspase-11 is sufficient to trigger endothelial pyroptosis and progression of ALI and fulminant pulmonary edema.  Thus, preventing endothelial pyroptosis and/or activation of endothelial repair may inform novel therapeutic approaches for ALI/ARDS. My projects are focused on the mechanisms underlying endothelial regeneration post endothelial injury in treatment of ALI/ARDS.

Xiaoyan Yang, PhD

Advisor:  Yulia Komarova, PhD

(1st year supported in training program)

Title:  The role of microtubule-associated protein 3 in endothelial signaling and injury

Abstract: We previously demonstrated that microtubule-associated end-binding protein 3 (EB3), a core component of the microtubule plus end protein network, binds to inositol 1,4,5-trisphosphate receptors (IP3Rs) and organizes calcium signaling in endothelial cells through assembly of IP3-induced IP3R clusters. Based on analysis of the EB3 - IP3R binding interface and computational alanine scanning mutagenesis, we have developed an allosteric inhibitory peptide (EBIN) that interacts with EB3 and inhibits its function. Furthermore, our in vitro experiments have demonstrated that EBIN attenuates agonist-induced calcium and nitric oxide signaling in endothelial cells. Consistent with the known role of calcium signaling in VEGF-induced cell migration and proliferation, treatment of animals with EBIN inhibited the ingrowth of new vessels into matrigel plugs implanted under the skin.  We next tested the pharmacological effect of EBIN using a laser-induced and choroidal neovascularization in mice. We found that EBIN treatment significantly reduced vascular leakage and neovascularization. Furthermore, using a lineage tracing Confetti reporter mice and multicolor live imaging, we are investigating the role of the peptide in regulating endothelial function in normal vessels and vascular diseases.