Project Title:  Traffic pollution and cerebrovascular disease in the Northern Manhattan Study
PrincipaI Investigator:  Mitchell S.V. Elkind, MD, MS, Professor of Neurology and Epidemiology
Co-Investigators:  Patrick Kinney, ScD, Dept. of EHS and Xinhua Liu, PhD, Dept. of Biostatistics, Columbia Univ; Gregory Wellenius, ScD, Brown Univ., Joel Kaufman, MD, MPH, Univ. of  Washington
Year:  2014-2015
Award Amount:  $25,000

Abstract:  Stroke is the leading cause of long-term disability and the fourth leading cause of death in the United States. Emerging evidence suggests that air pollution from traffic and other sources may be an important risk factor for and precipitant of adverse cardiovascular and cerebrovascular health effects. There are to date, however, few published large-scale studies specifically on the effects of traffic pollution on cerebrovascular endpoints. Moreover, clinical stroke is a devastating disease and important public health problem, but it only represents the most severe consequence of cerebrovascular disease; emerging evidence consistently demonstrate that subclinical cerebrovascular disease, manifested as white matter hyperintensities and silent infarcts on brain magnetic resonance imaging (MRI), is associated with cognitive decline, dementia, and functional impairment. In this pilot proposal to Columbia’s NIEHS Center, Dr. Elkind and colleagues propose to explore the effects of long-term exposure to traffic pollution on subclinical markers of cerebrovascular disease, including silent brain infarcts, brain atrophy, and white matter hyperintensities detected on brain MRI, in the Northern Manhattan Study (NOMAS). NOMAS is a large (n=3500), longstanding, multi-ethnic, prospective cohort study. Dr. Elkind is an experienced neurologist and vascular epidemiologist at Columbia, and a senior member of the Neurology and Epidemiology departments, but he is new to environmental health science research, has not previously published on health effects of traffic pollution, and has not yet collaborated with the Environmental Health Sciences Department. This proposal will provide an opportunity for the Columbia NIEHS Center to begin a collaboration with a longstanding neuroepidemiological cohort at Columbia University and develop preliminary data to permit a larger R01 proposal on pollution, acute stroke, and chronic cerebrovascular disease and cognition. Specifically, this new collaborative effort will bring together leading investigators at Columbia University (Drs. Mitchell Elkind (Neurology and Epidemiology), Dr. Patrick Kinney (Environmental Health Science), and Dr. Xinhua Liu (Biostatistics)), Brown University (Dr. Gregory Wellenius, Epidemiology), and University of Washington (Dr. Joel Kaufman, Environmental and Occupational Health Sciences, Epidemiology, and General Internal Medicine). Funding will support (1) obtaining measures of traffic pollution from existing monitoring data and validated models, drawing on the New York City Community Air Survey (NYCCAS) and the Multiethnic Study of Atherosclerosis-Air models; (2) a doctoral student to develop optimal measures of exposure based on available long-term monitoring data in the northern Manhattan community; and (3) preliminary analyses of the association of traffic pollution exposure measures and MRI findings.

Project Title:  New York City Commuters’ Peak Exposure to Black Carbon in-Transit and Associated Cardiovascular and Respiratory Health Effects
Principal Investigator:  Kyung Hwa Jung, PhD, Associate Research Scientist, Division of Pulmonary, Allergy and Critical Care of Medicine, Dept. of Medicine
Co-Investigators:  Rachel Miller, MD, Dept. of Medicine (in Pediatrics) and EHS and Matthew Perzanowski, PhD, Dept. of EHS
Year:  2014-2015
Award Amount:  $25,000

Abstract:  Exposure to traffic emission may trigger adverse cardiovascular and respiratory health outcomes. The public health implication could be substantial. This is especially true for commuters taking public transportation, and driving a car for a relative long time, given greater-than-average levels of black carbon (BC), a marker of traffic-related particles, observed inside buses, metro and cars and other forms of public transportation. Manhattan workers have the highest rate of extreme commuting (>=90 minutes each way to work on a regular basis). Seventy-five percent of all commuters to Manhattan take public transit (such as subway, buses, and rails) as their primary means of getting to work. To date, however, there has been very limited epidemiologic research on the health effects of short-term exposure to traffic emissions during a commute, a real-world high-exposure activity.

We hypothesize that long commute (>60 minutes per day) exposure accounts for a significant portion of an individual’s exposure to BC and a relative contribution to overall BC exposure differs by the mode of transport. In addition, we hypothesize that 1-2 hour peak exposure to BC during commutes is associated with increase in blood pressure, greater airway inflammation, and greater peak flow variability among New York City commuters. The aims are to a) Quantify the contribution of commuting activities to total personal daily BC exposure levels measured from direct readings from a real time BC monitor combined with time-activity pattern, b) Determine whether commuters’ exposure levels to BC differ by the mode of transport, and c) Explore whether short-term (peak) exposure to BC in-transit, or 24-hour averaged BC, is associated with elevated levels of blood pressure (BP), greater airway inflammation (measured by fractional exhaled nitric oxide (FeNO)), and greater peak expiratory flow (PEF) variability. Twenty-four healthy (free of cardiovascular and airway obstructive disease), non-smoking NYC commuters aged between 20 and 45, and spending at least 60 minutes or more in transit per day and taking either public transportation (e.g., bus, train, light rail or subway) or driving a car to work, will be recruited through advertisements posted on Columbia University. A sampling backpack that contains a sampling device will be dropped off at the participant’s work place and retrieved the following day by research personnel. BC levels will be measured by personal monitoring over a twenty-four hour period, including evening and morning commute periods. BP, FeNO, and PEF will be assessed four times: twice at the setup and takedown by research personnel and twice on arriving work and home by the participants. Perceived stress levels, assessed by a validated questionnaire, as well as other potential covariates (sex, age, obesity, second hand smoke exposure and others) will be controlled for the analysis. Findings from this pilot study would be used to support a larger scale study to understand how commuting, a real-world high-exposure activity, affect personal exposure to traffic-related air pollutants and associated cardiovascular and respiratory health effects.

Project Title:  Potential inhaled dose of particulates, biking and cardiovascular indicators
Principal Investigator:  Darby Jack, PhD, Assistant Professor of EHS
Co-Investigators:  Steve Chillrud, PhD, LDEO and Pat Kinney, ScD, Dept. of EHS
Collaborators:  Daichi Shimbo and Richard Sloan, Columbia Univ.; Jon Thornberg and Charles Rodes, RTI International; and John Keefe, Kio Stark, WNYC
Year:  2014-2015
Award Amount:  $25,000

Abstract:  The central goal of the proposed pilot is to establish the feasibility of procedures for measuring short-term air pollution exposures and acute cardiovascular outcomes in urban cyclists. If feasible, these procedures will form the core of an R01 proposal to be submitted in February 2015.

Biking is an increasingly important transportation mode in American cities, and municipal bike promotion policies make it likely that this trend will continue. While biking brings many benefits — increased exercise, less roadway congestion and reduced greenhouse gas emissions — it may cause increased exposures and doses to air pollution for those who choose biking over other transport modes. We seek to establish the feasibility of recently developed tools to assess exposures to traffic-related pollutants while cycling, and to deploy these methods in the context of a pilot study of the effects of air pollution exposure on important cardiovascular health indicators, including blood pressure (BP) and heart rate variability (HRV).

Air pollution exposures are of particular concern for urban athletes because they exercise in close proximity to traffic where pollution concentrations are high, and because respiration rates increase by a factor of 5 or more during vigorous exercise. The impact of increased respiration rates is critical because the inhaled dose of air pollution is roughly proportional to the respiration rate. Recent, low-burden personal real-time particulate matter (PM) monitors, with on-board accelerometers for estimating respiration rates, open the way for reliable estimation of real-time doses while riding bicycles. The current pilot proposal seeks to generate preliminary data in support of an R01 proposal that will test two hypotheses: 1) personal potential inhaled doses (concentrations of pollutant in the breathing zone x minute respiration rates) provide a better measure of health- relevant exposures than has previously been available (via ambient or personal exposure) and 2) potential inhaled dose of PM2.5 and BC during cycling affects BP and HRV responses.

In the pilot, study subjects will be recruited through our recent collaboration with WNYC. Drs. Chillrud, Jack, and Kinney started collaborating with WNYC in early 2013 with the goal of understanding air pollution exposures of urban cyclists in New York City. Initial data were collected on BC exposure during 13 commutes from Brooklyn to MSPH. Based on the large success that WNYC has had in the past on recruiting volunteers for crowd based measurements, the collaboration then formulated a plan whereby WNYC will recruit bicycle commuters over the air to participate in an exposure assessment. Interested riders will be directed to a website where they will answer a series of questions to determine their eligibility. WYNC will develop radio programming describing the process of data collection and summarizing the results. IRB approval was obtained late fall 2013 for the exposure assessment and we have begun the process to obtain IRB approval for adding in the additional monitors for collecting HRV and BP measurements.

In this pilot, we aim to demonstrate the feasibility of our techniques for measuring personal PM and BC exposures during bike commutes, and also for improving estimates of real-time inhaled dose using accelerometers built into the air monitors. We will also assess the feasibility and data quality of measuring ambulatory BP, HRV, and an independent measurement of minute ventilation rate.

Project Title:  Naturally occurring terpenes as a therapeutic strategy for cutaneous Squamous Cell Carcinoma
Principal Investigator: Ellen A. Lumpkin, Ph.D., Associate Professor of Somatosensory Biology (in Dermatology and Physiology and Cellular Biophysics)
Co-Investigators:  David M. Owens, Ph.D., Associate Professor of Epithelial Cell Biology (in Dermatology, Pathology and Cell Biology and Dental Medicine); Yalda Moayedi, Ph.D., Postdoctoral Fellow in the Department of Dermatology
Year:  2014-2015
Award Amount:  $35,000

Abstract:  Non-melanoma skin cancers are the most common tumors in humans. Concerns over the striking increase in skin cancer incidence have recently led to the Surgeon General’s Call To Action To Prevent Skin Cancer1. Cutaneous squamous cell carcinomas (cSCC) are invasive lesions, 10% of which carry a high propensity for metastasis. cSCC causes ~2,500 deaths annually in the US. One of the primary risk factors for cSCC is exposure to ultraviolet radiation (UVR). The current standard of care for cSCC is surgical excision followed by adjuvant radiation or chemotherapy; however, a subset of cSCC termed high risk can recur following surgery and are typically unresponsive to adjuvant therapy. This is particularly problematic in immunocompromised patients, whose incidence of high-risk cSCC is increased 60-100 fold. Epidermal growth factor receptor (EGFR) inhibitors have been recently FDA-approved for cSCC treatment; however, they show inconsistent efficacy and severe skin toxicity. Thus a major unmet medical need is novel therapeutic approaches for high-risk cSCCs. Our preliminary studies identify camphor oil, a mixture of structurally related terpenes, as a potent cSCC suppressor. Daily treatment with camphor oil slows malignant progression and causes dramatic

regression of pre-malignant tumors in a pre-clinical murine model of cSCC. Importantly, skin tumor regression induced by camphor oil is associated with a marked decline in the incidence of cSCC tumors. Here we aim to identify novel constituents of camphor oil that are effective in attenuating cSCC growth and are available at low cost to patients. We propose to 1) identify naturally derived, bioactive compounds in camphor oil that mediate tumor regression and 2) determine whether these common environmental chemicals reduce tumor burden by acting directly on keratinocytes or by altering aspects of the skin microenvironment. If successful, this pilot study will provide the basis for a novel and low-cost therapeutic method to treat cSCC.

Project Title:  Manganese Neurotoxicity in the Spinal Cord: Amyloid Precursor-Like Protein 1 and Motor Neuron Death
Principal Investigator:  Diane B. Re (aka Gourion-Arsiquaud), Ph.D., Assistant Professor of EHS
Co-Investigator:  Tomás R. Guilarte, Ph.D., Chair of the Dept. of EHS
Year:  2014-2015
Award Amount:  $35,000

Abstract:  Manganese (Mn) is a metal vital to human health as it is absolutely necessary for development, metabolism and antioxidant defenses. However, excessive Mn exposure or intake can cause a disorder of the nervous system called "manganism". This condition usually starts with psychiatric symptoms, such as compulsive behavior and emotional outbursts, before it progresses to a Parkinson's Disease-like syndrome, exhibiting difficulties in movement initiation and motor control. However, other symptoms of manganism, such as muscle weakness and impairment in fine motor control are more reminiscent of Lou Gehrig’s Disease, also known as Amyotrophic Lateral Sclerosis (ALS). Recently, brain imaging studies in young drug users injecting a home-made drug called ephedron, that contains high levels of Mn, revealed abnormalities close to those observed in ALS. In addition, exposure to high Mn levels has previously been suspected to contribute to the development of an inexplicably high number of patients affected by an ALS-parkinsonism-dementia syndrome in Guam and in the Kii Peninsula of Japan. In animals chronically exposed to Mn, it was shown to accumulate preferentially in areas of the brain that are selectively affected in Parkinson's disease and in the spinal cord. So far, Mn has been shown to cause neuronal death in diverse regions of the brain. However, the neurotoxicology of Mn in the spinal cord has never been investigated.

Dr. Guilarte, the co-investigator of this proposal, has been studying the neurological effects of chronic exposure of Mn in non-human primates for over 10 years. Dr. Guilarte and the principal investigator of this pilot study, Dr. Re, hypothesized that Mn may cause injury to the spinal cord and its connection to muscles, which could explain some of the ALS-like symptoms that were previously observed in animal models and humans. Accordingly, in specific aim 1 of this project, we will carry out the first investigation of the pathological effects of Mn in the spinal cord of macaques chronically exposed to Mn. Parenthetically, we should note that the spinal cord of control and Mn-exposed animals have already been collected and are available for immediate use. Specifically, we will assess Mn-induced neuronal death, inflammation, and protein aggregation in the spinal cord. These endpoints have been observed in other brain regions of Mn-exposed macaques, but this will be the first study of the spinal cord. Another common interest of Drs Re and Guilarte which is related to the second objective of this proposal pertains to a protein called Amyloid Precursor-Like Protein 1 (APLP1). In 2008, Dr. Guilarte described increased APLP1 levels in the brains of macaques treated with Mn. Independently, Dr. Re found that APLP1 was necessary for the induction of neuronal death when she was modeling ALS in a dish. More precisely, Dr. Re showed that astrocytes, brain cells which are normally supportive to neuron survival, become neuronal killers when the level of APLP1 increased. Thus, a natural question is whether or not increased APLP1 levels are also responsible for neuronal death upon Mn exposure. This hypothesis will be tested in specific aim 2, by treating brain astrocytes in a dish with Mn and assess their level of APLP1 and toxicity to neurons.

This Pilot Project will help Dr. Re, who is a junior investigator, to apply for a larger R01 to start a research program on the molecular and cellular mechanisms of Mn toxicity in the brain and the spinal cord. The senior co-investigator, Dr. Guilarte, who has an extensive experience in Mn neurotoxicity, will bring his critical expertise to the different phases of the project including the preparation of an R01 grant application.