Project Title: The Impact of Arsenic Exposure on the Progression of Chronic Pancreatitis to Pancreatic Cancer
Principal Investigator: Gloria H. Su, PhD, Associate Professor of Pathology and Cell Biology (in Otolaryngology/Head & Neck Surgery and in the Herbert Irving Comprehensive Cancer Center)
Collaborators: Helen E. Remotti, MD, Assistant Professor of Pathology and Cell Biology; Tom K. Hei, PhD, Professor of Radiation Oncology and EHS; Emily I. Chen, PhD, Assistant Professor of Pharmacology
Award Amount: $35,000
Abstract: Although pancreatic cancer is a relative rare cancer type in term of incidence, it’s the fourth leading cause of cancer death in the USA because 5-year survival for pancreatic cancer patients is at a startling low 6%. While it’s possible to monitor high-risk patients with the combined use of magnetic resonance imaging (MRI) and endoscopic ultrasonography (EUS), there is no cost-effective method to screen the general population for pancreatic cancer. But because pancreatic cancer is often fatal, patients are often diagnosed when the cancer has already metastasized, the ability to detect the cancer early is imperative for patient survival. Smoking and chronic pancreatitis (CP) are two major risk factors for pancreatic cancer, therefore it is logical to concentrate monitoring efforts on these demographics. While smoking is known to be a major risk factor for pancreatic cancer, the actual component in cigarettes responsible for the increased risk remains undefined. Similarly, the molecular events that are responsible for leading CP progression to pancreatic cancer are not understood. The prevalence of CP is about 50/100,000 per person and only a fraction of them will go on to develop pancreatic cancer, but there is no known predictor to identify individual CP patients who are more susceptible to developing the often fatal pancreatic cancer.
Arsenic may be a culprit for smoking-induced carcinogenesis and may augment the increased risks associated with CP. Arsenic, which is found in cigarettes and a proven human carcinogen, has recently been shown to associate with pancreatic cancer in epidemiology studies. Elevated arsenic measured in toenail samples was reported to be associated with increased risk for pancreatic ductal adenocarcinoma (PDA). Exposure to arsenic-contaminated drinking water wells was linked to increased risk for PDA. In a prospective study reported in 2013, arsenic exposure was prospectively associated with increased mortality for cancers of the lung, prostate, and pancreas. But arsenic has not been proven to cause pancreatic cancer biologically. Therefore, in Aim 1, we will use 3-D cultures of acinar cells isolated from two novel mouse models for CP and PDA to test if arsenic exposure will impact the acinar to ductal metaplasia (ADM) in vitro. In Aim 2, we will perform a pilot in vivo study on the CP model to investigate if arsenic exposure will exacerbate the CP phenotype and push the disease progression from CP to pancreatic cancer. We will also identify unique biomarker profile (exosomal proteins) that are specifically associated with this disease progression (from CP to pancreatic cancer) facilitated by arsenic exposure.
Our proposed research will be the first to provide the tangible evidence to establish the causal relationship of arsenic exposure to pancreatic cancer (Aims 1 & 2) and the first to provide a molecular predictor for CP progression to pancreatic cancer (Aim 2). The establishment of the causal relationship between arsenic and pancreatic cancer will significantly raise the awareness of the risks associated with arsenic exposure, particularly among CP patients. More importantly, the completion of our proposed research will promote new monitoring programs with novel biomarkers for high-risk patients.
Project Title: Carbon Monoxide Pollution and Fmr1 Gene Mutation: Exploring a Gene-Environmental Cause of Autism
Principal Investigator: Richard J. Levy, MD, FAAP, Professor of Anesthesiology and Pediatrics
Award Amount: $35,000
Abstract: Autism spectrum disorder (ASD) affects one in 68 children and is the fastest growing developmental disability in the US. The most promising hypothesis regarding the cause of autism suggests a gene-environment interaction. Recent studies indicate that exposure to traffic-related air pollution during gestation or early postnatal development is associated with increased risk of ASD. There is a major gap in our knowledge because it is unknown how air pollution interacts with specific genetic defects to result in the autistic phenotype. Fragile X syndrome (FXS), due to a mutation that results in transcriptional silencing of the Fmr1 gene, is the leading known genetic cause of autism. Fmr1 mutant mice have been developed to model human FXS, making Fmr1 ideal for the study of the gene-environment interaction. Carbon monoxide (CO) is a major component of motor vehicle-related pollution and a known neurotoxin. We have shown that CO impairs natural apoptosis in the developing wild-type murine brain, resulting in excess number of neurons, larger brains, memory and learning deficits, and relative social avoidance. In preliminary work, we also identified a defect in the mitochondrial pathway of apoptosis in the postnatal forebrain of male Fmr1 mutant mice. Therefore, this proposal will focus on the Fmr1 gene-CO interaction using a mouse model of FXS. Our specific hypothesis is that CO exposure during Fmr1 mutant brain development compounds and exacerbates defects in neuronal apoptosis and physiologic neuron elimination resulting in a well-defined autistic phenotype. The experiments are aimed at identifying the mechanism of CO-mediated inhibition of neuronal apoptosis in the Fmr1 knockout mouse forebrain and defining the behavioral phenotype of Fmr1 mutant mice exposed to postnatal CO. Success of the proposal will establish compounded defects in programmed cell death as a neurodevelopmental consequence of this specific gene-environment interaction and a contributor to the autism phenotype. Because this critical process is essential for normal brain development, we anticipate that data generated from this proposal will identify novel targets for therapeutic intervention.
Project Title: Improving data quality from low cost sensors
Principal Investigators: Darby Jack, PhD, Assistant Professor of EHS, Steve Chillrud, PhD, Lamont Research Professor, and Pat Kinney, ScD, Professor of EHS
Award Amount: $35,000
Abstract: Low cost sensors hold great promise in public health research, but their utility is currently limited by data quality problems. This is particularly true in the domain of air pollution epidemiology, where sensor networks will revolutionize exposure assessment if reliability can be achieved. We seek to pilot a new approach to addressing data quality problems arising in networks of low cost sensors. We propose to partner with Multitude, a software startup that has built a system that aggregates sensor data and pushes it through a series of correction algorithms. These algorithms draw both on prior knowledge about the physical properties of the sensors, and on coincidental and intentional collocation sensors in the field. We will use data from the current Columbia University air pollution and biking study and from regulatory monitors to validate this approach.
Abstract: Paraquat, the most widely used herbicide globally, is also an environmental and occupational toxin. Paraquat exposure results in damage to the lungs, kidneys, heart and liver, and in serve cases, respiratory failure and death. Emerging evidence indicates that there are links between long-term paraquat exposure and Parkinson’s Disease. We will use yeast as a model system to study the repair mechanisms that promote resistance to chronic, low-level exposure to paraquat. The proposed studies will extend our understanding of the consequences of paraquat exposure and reveal approaches to reduce the negative impact of this widely used environmental and occupational toxin.