Dr. Asrar B Malik

Schweppe Family Distinguished Professor & Department Head

Department of Cellular and Molecular Pharmacology


Office: 835 S Wolcott,  E403 MSB
email: abmalik@uic.edu
Phone: (312) 996-7636

Rotation Projects

Project 1: iPSC-Derived Human Lung Organoids: Modeling Homeostasis and Injury and Resolution The objective of this project is to develop and use a novel vascularized 3D human lung organoid platform and apply this system to study mechanisms of human lung development and disease. Human induced pluripotent stem cells (iPSCs) can be directed to differentiate into lung progenitor cells and further into mature lung cells. More recently, there has been a focus on placing iPSC-derived lung cells into a microenvironment mimicking human tissue during development and disease, such as novel lung-on-a-chip platforms or three-dimensional mini-lung organoid structures. However, most of the published lung organoid studies have focused on human iPSC-derived lung epithelial subtypes but do not include human iPSC-derived endothelial cells and are thus unable to adequately address the critical role of lung vascularization in lung development, homeostasis and disease. Based on preliminary data from our group, we hypothesize that human lung organoids generated by integration of human induced pluripotent stem cell (hiPSC)-derived epithelial and endothelial progenitor cells can be used to model human lung development and disease. We will study cell death, cell proliferation and metabolism of human lung endothelial and epithelial cells within the implanted lung organoids in response to LPS. We will also perform mechanistic studies on key mediators of inflammatory cell death and regeneration during ALI identified by us in genetic mouse models during the previous funding period to address mechanisms of injury and regeneration in human lung organoids.

The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation.

Project 2: Nanoparticle Targeting of Neutrophil Subpopulations in Inflammatory Lung Injury Acute Respiratory Distress Syndrome (ARDS) results from a severely dysregulated immune response that leads to lung vascular injury and protein-rich edema. Excessive activation of neutrophils (PMNs) is a primary cause of the lung damage. In experimental sepsis and septic patients, some PMNs are intensely activated and sequestered in lungs while others pass through the lung microvasculature unimpeded and function as essential host-defense cells. Previous findings suggest that PMNs might exist as various subsets and in different stages of activation. The concept of heterogeneity of PMNs raises the possibility that a subset of activated PMNs may contribute to a maladaptive inflammatory response and be responsible for lung injury. We found that a subset of PMNs specifically internalized 100 nm albumin nanoparticles (ANPs). This population of PMNs increased significantly in experimental sepsis in mice and they were shown to be essential for the development of inflammatory lung injury. We also conjugated drugs to ANP for their precise delivery into these PMNs. These results raise several fundamental questions: What is the nature of this PMN population? Is there a related population in humans? What is their function and what is their origin? What is the mechanism of ANP internalization? Do these cells mediate lung injury and can ANP deliver drugs into this PMN population to reverse the course of the disease? In this project we will define novel approaches to targeting neutrophils in systemic endotoxemia and sepsis using albumin nanoparticles and defining the distinct pro-inflammatory mechanisms of the PMN subpopulation characterized by high ANP uptake. These studies aim to not only define a population toxic injury-promoting population of PMN but also hopefully identify new therapeutic targets to reverse the course of inflammatory lung injury.

Endothelial cell Piezo1 mediates pressure-induced lung vascular hyperpermeability via disruption of adherens junctions.