2020 Pilot Project Awards
New Direction Pilot Project Award:
Principal Investigator: Qunwei Zhang, M.D., M.P.H, Ph.D.
Co-Investigator: Yiqun Mo, M.D., Ph.D.
Title: “Mechanisms underlying the susceptibility of diabetics to air pollution”
Description of Project: A number of epidemiological studies and animal experiments have also shown that individuals with preexisting diseases, such as asthma, diabetes mellitus (DM), and cardiovascular diseases are more susceptible to PM-related health problems. Individuals with DM may be more susceptible to PM because they have preexisting endothelial dysfunction and cardiovascular diseases. Hyperglycemia has been shown to activate macrophages/monocytes to secrete various cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor a (TNF-a), which are involved in various hyperglycemia-induced cardiovascular diseases. IL-1β has been well known as a proinflammatory cytokine involved in the pathogenesis of diabetes and atherosclerosis. Another family of molecules, matrix metalloproteinases (MMPs), are zinc-dependent endopeptidases that are considered to be responsible for the turnover and degradation of extracellular matrix. Breakdown of extracellular matrix plays a major role in the pathogenesis of atherosclerosis, including the early migration of monocytes into the arterial wall and the mechanical strength of the plaque cap. Few studies have focused on the activation of MMPs and the tissue inhibitors of MMPs (TIMPs) in macrophages/monocytes from subjects with DM with exposure to PM. The goal of this project is to test hypothesis that exposure to fine-PM in the setting of DM and high glucose will result in enhanced activation of macrophages/monocytes, with increased secretion of IL-1β altering the activity of MMPs and the tissue inhibitors of MMPs (TIMPs). We plan to use the data generated from this pilot study to develop and submit a NIH proposal in the following year.
Interdisciplinary Pilot Project Award:
Principal Investigator: Venkatakrishna Jala, Ph.D.
Co-PI: Mayukh Benerjee, Ph.D.
Title: “Microbial metabolites protect against arsenic induced gut barrier dysfunction”
Description of Project: Arsenic (As) is a naturally occurring pollutant and is widely distributed throughout the environment in the air, water and land. About 225 million people in over 70 countries in the world are chronically exposed to As. It is highly toxic in its inorganic form targeting liver, kidney, bladder, skin, and central nervous system as well as leading to carcinogenesis. The toxic effects of As on gastrointestinal (GI) system are poorly understood. It was shown that microbiota is required for protection against As-induced toxicity in rodent models. In vitro models suggested that sub chronic exposure of As induces intestinal epithelial barrier dysfunction and inflammation. Therefore, targeting intestinal barrier and inflammation synergistically will offer therapeutic options to mitigate As-associated toxicities. Recently, our group identified that some of the microbial metabolites enhance gut barrier function through upregulating tight junction proteins in addition to blocking inflammation. In this pilot project, we will test the hypothesis that treatment with specific beneficial microbial metabolites and their potent analogues mitigate arsenic-induced gut barrier dysfunction, inflammation and toxicity in gut epithelium. To test this hypothesis, Dr. Jala will collaborate with Dr. Mayukh Banerjee (member of CIEHS), who has over 15 years of hands on experience and a wide gamut of experimental expertise in the field of arsenic toxicity. We will systematically examine the cellular and molecular mechanisms in microbial metabolite-mediated protective activities against As3+-induced gut barrier dysfunction and inflammation. Upon successful completion of these pilot studies, we will establish protective activities of gut microbial metabolites against As3+-induced adverse events in gut epithelial cells for the first time. The data generated from this pilot project will provide strong supporting evidence for our hypothesis to apply for extramural funding.
Interdisciplinary Pilot Project Award:
Principal Investigator: C. Tyler Ellis, M.D.
Co-Invesigator: Natalie DuPre, Sc.D.; Matthew Ruther, Ph.D.
Title: “Identifying Geographic Clusters and Environmental Correlates of Colorectal Cancer (CRC) in Kentucky”
Description of Project: The goal of this project is to explore the role of environmental exposures correlated with colorectal cancer incidence in Kentucky, particularly for young-onset colorectal cancer for which risk factors are unclear. Early-onset colorectal cancer (20-49 years old) is on the rise in the United States, with incidence rates increasing from 8.6 per 100,000 in 1992 to 13.1 per 100,000 in 2016. This rapid rise cannot be fully attributed to genetic factors, which suggest environmental exposures, including occupational exposures, and lifestyle-related factors are driving this rise. The interaction, however, between these factors on the incidence of early-onset CRC remain unknown.
Kentucky has the second highest incidence rate of early-onset CRC at 14.2 per 100,000, trailing only Mississippi. In this proposal, we will use geospatial analysis to map out colorectal cancer cases in Kentucky using the Kentucky Cancer Registry database and identify clusters of disease by age distribution. The identification of hotspots of colorectal cases in Kentucky will generate hypotheses as to risk factors that may be at play. We plan to link the identified colorectal cancer clusters with publicly available databases to explore correlations between aggregated data on environmental factors (e.g. superfund sites, natural vegetation, hazard air pollutants), neighborhood socioeconomic factors, and lifestyle factors (e.g. obesity, physical activity). We will use these data to explore ecological associations between environmental exposures and colorectal cancer incidence. Our results will serve as preliminary data to propose a larger grant application to ascertain individual-level environmental, socioeconomic and lifestyle factors.
Career Development Pilot Project Award:
Principal Investigator: Mayukh Banerjee, Ph.D.
Title: “APC11 is a novel target for arsenic-mediated zinc displacement leading to cell cycle disruption”
Description of Project: Over 225 million individuals globally, including 2.9 million in USA are chronically exposed to arsenic from environmental sources, leading to multi-organ cancerous and non-cancerous adverse health outcomes. Skin is the major target organ, with well-characterized non-cancerous, pre-cancerous and multiple cancer outcomes. While several mechanisms are postulated to be responsible for arsenic-induced carcinogenesis, a clear picture is yet to emerge. Disruption of cell cycle progression through altered cyclin expression is a universally accepted mechanism, but how arsenic mechanistically brings about such changes remain to be explored. Employing a well-established model of arsenic-induced skin cancer (HaCaT cells exposed continuously to 100 nM sodium arsenite for 28 weeks), RNA-seq and pathway analyses, we demonstrated that arsenic altered multiple cell cycle regulatory pathways simultaneously suggesting abrogation of cell cycle progression. Many of these dysregulated pathways engage in extensive molecular crosstalk by sharing key regulatory cyclins. Normal cell cycle progression is tightly coordinated by regulating the ubiquitination mediated degradation of cyclins in a cell cycle phase specific manner. Cyclosome (APC/C) is a key multi-subunit E3 ubiquitin ligase regulating degradation of several cyclins, ANAPC11 being the catalytic subunit responsible for ubiquitination function. ANAPC11 contains a RING finger type zinc finger domain that is essential for its ubiquitination function. Arsenic displaces zinc from zinc finger domains of proteins including from RING fingers. We hypothesize that ANAPC11 is a target for arsenic mediated zinc displacement. Such zinc displacement will abrogate ANAPC11 function leading to stabilization of cyclins and cell cycle disruption, a common feature in arsenic carcinogenicity. The present proposal aims to: (1) Determine if As3+ exposure interferes with the expression and degradation of cell cycle regulatory protein targets of ANAPC11; (2) Determine if ANAPC11 is a target for As3+ toxicity; (3) Develop and validate model systems to assess the biological effects of As 3+ exposure on ANAPC11 and subsequently on cell cycle disruption. Successful execution of the current proposal will substantiate the possibility that arsenic exposure brings about skin cancer by disrupting the function of cell cycle regulating E3 ubiquitin ligases. The outcomes from this study will allow us to prepare a competitive application for NIEHS R01 funding. In the proposed R01, we will evaluate the role of Zn2+ displacement from cell cycle regulating E3 ubiquitin ligases as a critical missing link between As3+ exposure, global cyclin stabilization and cell cycle proteome change, leading to cell cycle disruption and carcinogenesis and zinc supplementation as a possible intervention.
Community-Engaged Pilot Project Award:
Principal Investigator: Edrisa Sanyang, Ph.D.
Co-Investigators: Ritchie Taylor, Ph.D., Gretchen Macy, Ed.D., Vijay Golla, Ph.D., Luz Huntington-Moskos, Ph.D., R.N, C.P.N., Ruth Carrico, Ph.D.
Title: "Firefighter Practices and Exposure in Response to Covid-19 in Northwestern Kentucky"
Description of project: Firefighters are at high risk of health hazards due to occupational practices and work-related exposures. As frontline workers, firefighters must make decisions based on incomplete information to provide care in heterogeneous, and often uncontrolled, circumstances. The Coronavirus Disease 2019 (COVID-19) pandemic further challenges first responders to develop and implement policies to control/minimize exposure specific to COVID-19, as well as other biological hazards. To this end, fire departments are under increased pressures, including providing and ensuring proper use of personal protective equipment (PPE), understanding how to navigate and prevent infectious diseases transmission during response to calls and in the dayroom, and managing stress associate with pandemic-related emergency response in their respective communities. The Western Kentucky University Center for Environmental and Workplace Health (CEWH) research team previously identified firefighter exposures to work-related toxic substances and behaviors related to the management of turnout gears (coats and pants); however, little is known about controlling biological hazards in fire departments and during emergency response activities.
This pilot study will obtain a comparison outlook of career and volunteer firefighter knowledge to COVID-19 transmission by investigating any gaps in knowledge on infection control in the dayroom, emergency response vehicles, and during runs. This will include assessing current knowledge of infection control including PPE use. Secondly, we will investigate the fire department’s preparedness for COVID-19 and assess overall worksite response changes due to COVID-19. Results from this pilot study will be used by a consortium, including researchers at the Western Kentucky University Center for Environmental and Workplace Health (CEWH), the University of Louisville Center for Integrated Environmental Health Science (CIEHS), and the Green River Fire Association (GRFA), to develop a collaborative competitive research agenda.
This study aligns with the National Institute for Occupational Safety and Health (NIOSH) priority area on infection control in healthcare including first responders. Moving forward, data will be collected from an intervention study on infection prevention and control in the workplace, and during emergency response. Ultimately, we will develop best practices that will protect career and volunteer firefighters, which will improve their training curriculum. These data will help inform the development of policies that will improve the safety of firefighters and support high-quality service provision to the community.