Sally Wenzel - Department Chair
Our laboratory has focused on understanding both the subtypes of human asthma and the combination of environmental and genetic factors which drive them. Research has focused on the role of airway epithelial cells in human disease, given the position of these cells to link the environment with the host. Work encompasses use of large epidemiologic/research databases, including those both local and national, to define patient characteristics and relationships to environmental triggers, but also to include studies of specific human immunology, both in human samples and model systems. Current pathways of interest include those related to environmental and innate lung oxidative stress, as well as their intersections with inflammation, mucins and cell death pathways.
Wenzel was chosen as the American Thoracic Society Amberson Lecturer in 2021. The Amberson Lecture recognizes exemplary professionalism, collegiality and citizenship through mentorship and leadership in the ATS community. The Amberson Lecturer is an individual with a career of major lifetime contributions to clinical or basic pulmonary research and/or clinical practice. The lecture is given in honor of James Burns Amberson, an international authority on chest disease and tuberculosis.
My professional journey has been defined by a fervant commitment to understanding and mitigating the impacts of environmental factors on population health, particularly within vulnerable groups, such as pregnant women and children. Originating from Suriname, I bring a unique perspective to my population health research, which centers on the intricate interplay between chemical exposures (such as pesticides, heavy metals and PFAS), climate change, as well as food security and safety. A cornerstone of my research endeavors revolves around the profound impact of nutrition on neurodevelopment, particularly among children prenatally exposed to metals like mercury and lead in Suriname. Looking ahead, my research trajectory is resolutely focused on the dynamic and pressing challenges posed by climate change, both locally and globally. I am deeply invested in deciphering the multifaceted impacts of climate change on health, such as the combined effect of heat exposure and pesticide exposure on kidney health. In essence, my work strives to bridge the gap between environmental health research and actionable solutions that promote better health outcomes.
The primary focus of current research is investigating the cellular and molecular mechanisms underlying human blood vessel and lung diseases caused by environmental exposures to metals and chronic changes in redox status. In vivo and cell cultured-based studies focus on the molecular pathology and etiology of vascular disease caused by chronic exposure to low levels of arsenic in drinking water. The cell signaling pathways that mediate arsenic stimulated pathogenic phenotypic changes in endothelial cells are being investigated. Additional studies examine the molecular signaling mechanisms mediating gene induction and silencing in airway epithelial cells exposed to chromium. The objective of these studies is to identify the pathways through which inhaled chromium aggravates lung injury from infections and exposure to other metals.
My research focuses on understanding many aspects of environmental toxicology, including both the fate, bioaccumulation, phase I & II metabolism, excretion, and effects of toxic substances such as metals. Other research areas include isotope ratios and epidemiological studies investigating the association between exposure to Pb, As, and PAHs, and occurrences of chronic kidney disease and respiratory outcomes.
My research is focused on understanding/deciphering deciphering the mechanisms of lipid peroxidation triggered programmed cell death pathways- ferroptosis/necroptosis and their regulation in the context of diseases/injury imposed on tissues like lungs, gut, and brain cortex by different insults- environmental, chemical, physical or biological. Decoding these mechanisms will lead to identification of new drug intervention targets and are crucial for the development of specific drugs and diagnostic procedures. At present the focus is to explore ferroptosis in the context of host-pathogen interaction and using Pseudomonas aeruginosa as a model, investigate the pathogen induced theft-ferroptosis as a virulence mechanism particularly in immune compromised patients within hospital environment, in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
The primary goal of my laboratory is to develop peptide-based antimicrobial therapeutics against multidrug-resistant bacteria. Antibiotic resistance constitutes a global health crisis, which threatens to reverse many advances in the field of medicine. In that regard, cationic antimicrobial peptides (AMPs) are a class of antimicrobial agents that are very promising therapeutics against multidrug-resistant (MDR) bacteria-related infections because of their ability to directly disrupt bacterial membranes and their lower propensity to invoke selection of resistance compared to conventional antibiotics. However, cationic peptides present several challenges related to their susceptibility to protease digestion and to their lack of activity in certain types of biological environments (e.g., divalent cations, blood). While sequence optimization or de novo engineering can help overcome some of these limitations, AMP design is currently done mainly by trial and error based on the principle of cationic amphipathicity. Thus, the future of this promising class of therapeutics depends on the ability to design AMPs for specific applications by dissecting the AMP functional motifs to uncouple their dual properties of antimicrobial activity and host toxicity. In my laboratory, we are addressing this challenge through iterative structure-function correlations to minimize peptide length required for optimal antimicrobial activities and negligible toxicity to mammalian cells, which will result in high antimicrobial selectivity index. Data are usually streamlined to select candidates that display systemic efficacy with a high therapeutic index in small animal infection models.
My research aims to investigate the effects of environmental exposure on the host. We are particularly interested in infection and immunity in the lung and the associated pathophysiological response during injury, repair, and regeneration. My lab's primary research focuses on the cellular and molecular actions of environmental or occupational exposures to toxic chemicals and microorganisms that underlie the pathogenesis of chronic human lung diseases. The three main areas of my lab research are 1) elucidating antimicrobial resistance (AMR) mechanisms and developing novel antibiotics to overcome AMR; 2) studying the pathogenesis of environmental exposure and host immunity in human diseases, including asthma, CF, and COPD; and 3) investigating inflammation-associated tissue injury and remodeling and lung tumorigenesis. We research the normal and pathogenic interactions between the body's cells concerning the environment by harnessing the knowledge of lung biology, immunology, cellular and molecular biology, and state-of-the-art technologies to develop and integrate systematic and innovative approaches.
My overall research mission is dedicated to the investigation of cellular mechanisms by which various environmental agents, particularly those that affect the lung, perturb cell physiology, and, thus, contribute to organ dysfunction during toxicity. Only by understanding the cellular and molecular mechanisms of toxin action can effective chemopreventive and therapeutic strategies be designed. Of primary current interest is the role of oxidative stress, not only as a mediator of cellular damage, but also as a physiologic signaling mechanism that can dictate numerous cellular responses.
Neurodegenerative diseases are complex multifactorial diseases with identified genetic determinants along with environmental influences and life-style choices. My research is focused on understating how the exposome and associated genetic factors interact to modify normal brain development, healthy brain aging and the molecular pathogenesis of neurodegeneration. APOE and TREM2 are major risk factors for Alzheimer’s disease so I am particularly interested in uncovering their role in glial function, lipid and cholesterol transport, neuroinflammation and associated pathologies. I use broad approaches with primary glial culture, transgenic mouse models, and Alzheimer’s disease patient samples and data, -omics including CHIPseq, RNAseq, single cell RNAseq, spatial RNAseq, lipidomics, in vivo microdialysis, and complex imaging.
Kagan’s laboratory and Center for Free Radical and Antioxidant Health has been studying redox mechanisms of physiological processes in cells and tissues as well as their aberrant changes caused by exposure to environmental factors and disease conditions. The major focus of this work is on phospholipids and their role in signaling. The Lab has developed highly sensitive and specific LC-MS based protocols for the detection, identification and quantitative analysis of oxidatively modified lipids. With this technological advancement, the major efforts are directed towards understanding and deciphering the signaling language of peroxidized phospholipids. Among the most advanced areas of research are studies of phospholipid signals in programs of regulated death such as apoptosis, necroptosis and ferroptosis. This work resulted in the discovery of new mechanisms of cell death in acute brain injury, acute radiation syndrome, pulmonary diseases (including ARDS, asthma and bacterial pathogen/host interactions in the lung), organ transplantation. Another aspect of the current work is related to decoding of mechanisms of lipid reprogramming of innate immune cells in tumor microenvironment leading to immunosuppression of myeloid cells in cancer. Unearthing of new enzymatic mechanisms of redox phospholipid signaling leads to the design and development of new therapeutic modalities. This work is also going on in the Lab.
I am studying the role of lipid peroxidation in the control of cell death with focus on understanding of the role of enzymatic lipid peroxidation in regulation of ferroptosis and apoptosis.
Our laboratory uses broad approaches to dissect regulatory networks and to explore the role of lipid-associated genes and proteins in molecular pathogenesis of Alzheimer’s disease.
Current projects relate to genetically modified mouse models of Alzheimer’s disease (AD) and cholesterol metabolism. A particular focus is on liver X receptors (LXR). Their regulatory function in the brain in health and disease is being approached using complex transgenic mouse models of altered lipid metabolism. Behavioral phenotyping and histopathology are used to reveal clues of LXR-controlled regulatory networks in the brain. Age-dependent and disease-related changes in immediate early genes (IEG) response to environmental factors is the second major research theme. Molecular, pharmacological, and genetic approaches; gene profiling; and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) in intact animal models of AD are being used to assess IEG-controlled signaling pathways. AD pathogenesis in those models is assessed in the context of gene-environment interactions genome-wide using high-throughput genomic and epigenetic tools, diet, and dietary manipulations.
Maureen Lichtveld - Pitt Public Health Dean
As a physician scientist and member of the National Academy of Medicine (NAM), I have over 35 years of experience in environmental public health and health disparities research. My research focuses on environmentally-induced disease, health disparities, community-based participatory research, climate and health, community resilience, environmental health policy, disaster preparedness, and public health systems. My track record is in environmental epidemiology studies with a special emphasis on persistent environmental health threats affecting health disparate communities and disaster management. For example, I serve as PI on a project which linked implementation research and research training grants designed to identify exposures to a complex mixture of developmental neurotoxicants including mercury, arsenic, lead, and selected pesticides through comprehensive dietary, environmental, and health risk assessments, and biomarker monitoring in 1200 mother-child dyads. I have extensive experience in the development, implementation and monitoring, including recruitment and retention of large environmental epidemiological cohorts (EEC).
My research focuses on understanding and illuminating environmental health disparities and policy mechanisms that can mitigate impacts. I have an emphasis on cumulative impacts of environmental stressors and focus my research on the two core tenets of environmental justice- meaningful engagement and fair treatment. I am currently researching air quality impacts in areas with higher environmental justice burdens and the efficacy of public engagement in the development of national air quality standards. I also study and promote engagement efforts that build environmental health literacy.
Our lab examines how environmental exposures during susceptible periods of life (perinatal to adolescence to pregnancy to postpartum) can impact kidney development and function that predict chronic disease. Our research uses novel methods to examine complex chemical (e.g., metals, air pollution, fluoride) and non-chemical (e.g., heat, stress, sleep) risk factors for kidney dysfunction among susceptible populations including pregnant women, children, agricultural workers as well as diverse populations with chronic kidney disease.
My current research focuses on deciphering how environmental stressors (chemicals and non-chemicals) and dietary factors can epigenetically alter gene activity in a life-time manner, leading to complex diseases. These epigenetic changes can persist after the exposure has stopped to cause long-lasting effects on development, metabolism, and health, sometimes even in subsequent generations. My long-term goal is to apply innovative and promising epigenetic approaches to understand the underlying mechanisms by which epigenetic changes may contribute to common diseases. Our findings may lead to the development of improved preventive measures and therapeutic strategies to reduce the burden of chronic diseases. Also, translating our scientific findings into human may provide proper disease management and lifetime recommendations to the public. Current funding/projects: 1) Explore the role of DNA hydroxymethylation in asthma pathogenesis; and 2) Understand the impact of early-life exposure to inorganic arsenic (in drinking water) on later-life asthma risk.
My goal is to elucidate the molecular mechanisms through which lipid metabolites regulate cellular membrane structures as well as membrane-bound complexes, particularly under conditions of oxidative/nitrosative stress.
My primary research is concerned with the role of free radical reactions and, more specifically, the role of lipid peroxidation in apoptosis.
My research interests are focused on the translational study of asthma using primary human epithelial cells as a model, particularly the role of T2/15LO1/autophagy/ferroptosis as related to asthma pathogenesis. My research interests also include the effects of respiratory virus infection in human airway such as Influenza, Rhinoviruses, and SARS-CoV-2. We are currently working on a NIH-funded project to investigate the 15LO1-dependent ferropsutotic mitochondria damage and cell death, and have published a series of key publications in prestigious journals such as Cell, PNAS and JCI.