2011
Project Title: Examining the Effects of Chlorpyrifos on Attention and Neurodevelopment”
Principal Investigator: Jonathan Posner, MD, (Assistant Professor of Clinical Psychiatry)
Year: 2011
Award Amount: $25,000
Abstract: This study aims to examine the effects of prenatal exposure of chlorpyrifos (CPF) on neuroanatomical correlates of attention. The study will be conducted in collaboration with Drs. Virginia Rauh and Bradley Peterson, who are currently carrying out an R01-funded prospective study of the impact of environmental pollutants on brain development. As part of the Rauh–Peterson study, resting-state functional magnetic resonance imaging (rs-fMRI) scans have been obtained in 40 children at ages 7–9 for whom CPF levels in umbilical cord blood have been recorded. For the funded pilot, funds were requested to process and analyze 40 rs-fMRI scans, 20 children with high and 20 with low levels of CPF exposure. The goal is to examine the influence of CPF on the neural connectivity of the brain’s default mode network (DMN)—a neural network critical in establishing attentional regulation. The principle hypotheses are that in the children who are CPF prenatally exposed vs those who are unexposed, elevated symptoms of inattention and hyperactivity and altered neural connectivity within the brain’s DMN will be found; and that finally the altered connectivity within the DMN will mediate the relationship of CPF exposure with the symptoms of inattention and hyperactivity.
Project Title: Function of Hairless in UV-induced Skin Cancer Susceptibility
Principal Investigator: Liang Liu, PhD, Associate Research Scientist, Dept. of Dermatology
Co-Investigator: Angela Christiano, PhD, Professor in the Dept. of Dermatology
Year: 2011
Award Amount: $25,000
Abstract: Non-melanoma skin cancer (NMSC), including squamous cell (SCC) and basal cell (BCC) cancers, is the most prevalent type of human cancer. A well-known, common cause of skin cancer is excessive exposure to UV irradiation from sunlight that can cause DNA damage, inflammation, skin aging, and eventually skin cancer. Multiple signaling pathways and transcription factors have been investigated to understand the connection between sun exposure and skin cancer, however, the exact mechanisms underlying UV action in promoting skin cancer development await further exploration. Another priority in skin cancer research is to identify novel molecular targets for chemoprevention and therapy of skin cancer. The hairless gene is a key regulator of the balance between cell proliferation and differentiation in the skin. Mutations in hairless cause permanent hair loss in both humans and rodents. Mice that harbor functional mutations in hairless are extremely susceptible to developing skin cancer in response to UV irradiation. Microarray analysis of hairless-mutant versus wild-type mouse skin identified genes that are regulated by hairless including cell cycle regulation and apoptosis genes, and in particular, numerous genes that are known targets of NFκB signaling. These novel findings, together with our previous observations of dysregulated apoptosis in the hair matrix of hairless mutant mice, strongly suggest that loss of hairless function in the skin may play a causal role in skin photocarcinogenesis.
In this proposal, we will test the hypothesis that hairless is a key regulator of the balance between cell proliferation and differentiation via its novel role as an epigenetic regulator of target gene activity. We will attempt to address the following three essential questions: 1) how does hairless function in the skin; 2) does hairless control cancer growth via regulating the activities of other genes; 3) can we reduce UV-induced skin cancer incidence by restoring or enhancing hairless function in skin cells?
Project Title: Investigation of a role for manganese in regulating mitochondrial dynamics
Principal Investigator: Liza Pon, PhD, Professor, Dept. of Pathology and Cell Biology
Co-Principal Investigator: Chun Zhou, MD, PhD, Associate Research Scientist, Dept. of Pathology and Cell Biology
Year: 2011
Award Amount: $25,000
Abstract: Neurodegenerative diseases are among the most pressing challenges facing the ageing populations of developed nations. Parkinson's disease (PD), the second most common neurodegenerative disease, is associated with movement disorders and cognitive disorders with dementia commonly occurring in the advanced stages of the disease. A number of risk factors have been identified that predispose individuals to PD. For example, exposure to certain pesticides or herbicides (e.g. Agent Orange) can double the risk for PD. Emerging evidence indicates that exposure to heavy metals may also be a risk factor. Manganese (Mn) is an essential nutrient. However, at high levels Mn is toxic and produces a severe, debilitating neurological disease that resembles PD. Chronic exposure to low levels of Mn leads to defects in motor coordination of fine movements. Moreover, one of the pesticides that increases the risk of PD contains Mn. These findings have led to the model that chronic lifetime exposure to very low levels of Mn is a PD risk factor. We propose to study the mechanism underlying Mn toxicity and the effect that Mn has on mitochondria, the organelle that produces energy in cell. Neurons, including those that are compromised both in PD and upon Mn exposure, have high-energy demands and are severely compromised by defects in mitochondrial function and by defects in localizing functional mitochondrial to their sites of action within cells. Moreover, Mn is known to have effects on mitochondrial energy production. Our central hypothesis is that excessive Mn impairs mitochondrial function at the pre-synaptic terminals, through effects on mitochondria, transport or anchorage of mitochondria in the pre-synaptic terminal of dopaminergic neurons and/or effects on mitochondrial fusion/fission and autophagy at this site. This in turn diminishes local ATP synthesis or calcium buffering required for normal dopamine release. We propose to study the effect that Mn has on mitochondrial function and localization in pre-synaptic structures in primary dopaminergic neurons. We will study how Mn affects mitochondria function within the context of the living cell and assess the role of autophagy and mitochondrial fusion and fission, processes that can lead to degradation of dysfunctional mitochondria, in elimination of Mn-damaged mitochondria. We also will determine whether mitochondria are mislocalized after Mn treatment, and use live cell imaging to determine whether the mislocalization is due to defects in motility and/or anchorage of mitochondria in axons and the presynaptic terminal. Finally, we will determine which of these machineries plays the most prominent role in Mn-induced mitochondrial toxicity. The proposed studies will extend our understanding of how environmental factors contribute to or pre-dispose individuals to PD. In addition, the molecules involved in the Mn-induced defects of mitochondria, once obtained, will serve as potential therapeutic targets for a cure.
Project Title: Exposure to Elevated Levels of Combustion-Related Air Pollutants and Asthma among Non-Atopic Children in Beijing, China
Principal Investigator: Beizhan Yan, PhD, Lamont Assistant Research Professor
Year: 2011
Award Amount: $25,000
Abstract: In our NYC asthma studies, substantial efforts have been made to examine associations between exposures to incomplete combustion-related air pollutants (e.g., polycyclic aromatic hydrocarbons (PAHs), black carbon (BC) and metals) and asthma symptoms. Recent work has extended these efforts to investigate biomarkers of airway inflammation and oxidative stress in exhaled breath condensate (EBC) as biomarkers of effect. Observed associations appear to be stronger among the non-atopic children (i.e., those without sensitization to inhalant allergens). Due to the higher and wider range of concentrations of combustion byproducts in China than those found in NYC, studies carried out in China can aide in understanding the relationship between exposure to combustion byproducts and the biomarkers of inflammation and oxidative stress, measurement of which are being developed in Dr. Yan’s laboratory in collaboration with Dr. Perzanowski. The proposed pilot study will recruit 30 non-atopic asthmatic children, ages 9-10, in central Beijing and an outer suburb so that the study population will live in areas with a wide range of air pollution levels. Indoor and outdoor PM2.5 filter samples will be collected and personal exposure of black carbon will be monitored in two sampling periods (one week in heating season and the other in non-heating). Lung function and biomarkers of airway inflammation and oxidative stress in EBC will be measured in the end of each sampling period. Columbia will loan sampling devices and provide necessary training in field and laboratory methods to Dr. Xu from the China CDC; Dr. Xu and her team will conduct the fieldwork and biomarker analyses. The overall goal of this pilot study is to demonstrate the feasibility of environmental asthma studies in Beijing through collaboration between Columbia University and the China CDC and generate pilot data.