Co-authors: Hoda Anton-Culver, PhD, Professor and Chair, Dept. of Epidemiology, Director, Genetic Epidemiology Research Institute
Agyrios Ziogas, Ph.D., Associate Adjunct Professor, Dept. of Epidemiology
Employment records are used to form historical occupational cohorts to study chronic health outcomes such as cancer due to occupational exposures. However, employment records are not collected with the intention to be applied in epidemiological studies, and therefore a number of variables important for association studies need to be reconstructed from other sources. The objective of this study is to generate an occupational cohort with exposure information and assess etiological factors for various health outcomes including cancer. The Long Beach Naval Shipyard (LBNSY) consists of approximately 44,000 employment workers from 1978 to 1985. The LBNSY cohort consists of 13,935 records that have been digitized. In addition, a subsample of 1,763 workers participated in a survey, which we are using for validation of some variables. In our study, we are using public databases to examine occupational exposures at the shipyard over a long time period since 1978 and examine morbidity and mortality outcomes with a focus on cancer incidence. We used information from employment rosters and the survey to determine job exposures based on job titles. The survey contained assessment of 23 different occupational exposures in the LBNSY. Each job title was standardized based on the Standard Occupational Classification from 1983. Exposures to various occupational agents were assigned for each shop (job location) based on the information from the survey and on the occupations in each of the shop. Furthermore, we validated a modified method previously proposed in 1983, which used Florida phosphate workers cohort, to predict the year of birth of individuals in our cohort with unknown date of birth using Social Security Number. After validation the method were applied to individuals with missing age. We also linked the employment records with the California Cancer Registry and death file to determine cancer incidence and mortality. There are 3,690 deaths and 1,899 observed cancer incidences in the cohort. In conclusion, occupational cohorts are an important source of information in evaluating the long-term effects of exposures to multiple occupation agents. Chronic diseases such as cardiovascular diseases and cancers take several years after exposure to manifest. Historical occupational cohorts is economical and allows the ability to examine diseases with long latency period. However, employment records used in these cohorts were not collected for the purpose of research and have several limitations. Our study presents different approaches to add more informative data in an occupational cohort to assess etiological factors for chronic health outcomes.
Co-authors: Mónica Romero López (Biomedical Engineering, UCI), Steven George (Biomedical Engineering, Washington University, St. Louis), Christopher Hughes (Molecular Biology and Biochemistry, UCI)
Cellular therapies using heart muscle cells (HMC) created from stem cells have great promise in treating heart disease, which is the number one cause of death in the US. There are many advantages to using stem cells, which include the ability to convert patients’ own cells into stem cells, access to unlimited number of cells, and that they can become almost any cell type in the human body, including heart muscle cells. Unfortunately, it is well established that stem cell-derived HMC are immature with characteristics of fetal heart cells rather than adult heart cells. These characteristics include disorganized structures, spontaneous beating, improper signaling and different responses to pharmaceutical drugs compared to mature HMC. Consequently, it is considered less than ideal to use immature stem cell-derived HMC for cellular therapies due to safety concerns arising from the cells’ immature state. It is necessary therefore to understand what influences HMC maturation, and to find strategies to mature the stem cell-derived heart muscle cells so that they may be effectively and safely used for transplantation. We are exploring the possibility that a tissue’s natural scaffold and blood vessel cells drive HMC maturation and behavior in the same way they drive maturation of organs such as liver and pancreas. We have generated heart scaffolding from cow heart tissue by removing all cells from the tissue, and find that the heart scaffolding affects stem cell-derived HMC maturation, based on enhanced expression of mature HMC markers. In addition, we have also seen increased levels of maturation when the stem cell-derived HMC are seeded into a three-dimensional heart scaffold compared to two dimensions. We are now studying how the heart scaffold and blood vessels work in concert to affect HMC maturation. Taken together, these studies will help develop mature stem cell-derived HMC that can be effectively used for drug screening, and safely used for cellular therapies to treat heart disease. Lastly, the results of this research will help advance the tools necessary to treat the millions of current and future heart disease patients.
Co-authors: Robert V. Warren (Biomedical Engineering), Pietro Galassetti (Pharmacology), Shaista Malik (Cardiology), Bruce J. Tromberg (Beckman Laser Institute)
Obesity and its large prevalence constitute one of the gravest threats to public health in the United States today. While it is well known that obesity is a risk factor for the development of diabetes and heart disease, the precise mechanisms by which it leads to these complications are not fully understood. Recent evidence points to the role of fat tissue itself as a potential culprit in this process. Some hypothesize that as fat cells become increasingly large with overall weight gain, they also become less efficient at utilizing oxygen, and that this can lead to hypoxia and inflammation. However, there are currently no tools available to study fat tissue in humans non-invasively. Therefore, we hypothesized that diffuse optical spectroscopy and imaging (DOSI) could be used to measure changes in structure and function of subcutaneous fat tissue. DOSI is a portable device that measures the near-infrared scattering and absorption of tissue using a probe placed on skin. Generally, scattering properties reflect tissue structure whereas absorption relates to tissue blood supply, oxygenation, and water.
To test our hypothesis, we recruited participants from those participating in a medically-supervised weight loss program. We use DOSI to measure the abdominal fat tissue at several points over the course of weight loss. Additionally, we used ultrasound to characterize the thickness of fat tissue, and also measured weight, blood pressure, and abdominal circumference.
Results: A total of 8 subjects have participated in this study, and they have experienced an average weight loss of 11.3% of their starting weight. We found that weight loss is associated with significant changes in the way that light is scattered in fat tissue, indicating a decreased size and increased density of scattering events. Furthermore, there is an elevated concentration of hemoglobin and water with weight loss.
Conclusion: It is likely that the changes detected using DOSI reflect both the reduction in fat cell size and increase in fat metabolism that are known to occur with weight loss. While at this time we have no histological evidence for these processes, they have been observed by others using different techniques. These findings are important because they suggest that DOSI could be used to non-invasively and longitudinally assess the effects of treatments on the risk of complications from obesity. Ultimately, this might be useful in both the assessment and screening of treatments for obesity and diabetes for effects on fat tissue function.
Co-authors: Roxana Khalili, Scott Bartell, Verónica Vieira
Particulate matter less than 2.5µm in diameter (PM2.5) can alter immune function making individuals, especially infants, more susceptible to illness. Outdoor air PM2.5 is a mixture of particles from vehicle exhaust emissions, industrial activities, and coal and wood burning, and levels are typically highest in the winter. The goal of this work is to determine if short-term exposure to PM2.5 is associated with infant bronchiolitis, the leading cause of hospitalizations in the first year of life, among all infants born in Massachusetts between 2001and 2009. Average daily PM2.5 concentrations for all of Massachusetts were modeled using satellite remote sensing data. We analyzed 11,805 hospitalization records of infant bronchiolitis using a case-cross over study design where cases serve as their own controls. Using this study design, only variables that change during the short-term, such as the temperature and humidity, need to be considered in the analyses along with exposure. Results indicate that for an additional 10 µg increase of PM2.5 , infants were 6 to 28% more likely to be hospitalized for bronchiolitis, depending on gestational age and seasonality. Infants born prematurely between 32 and 37 weeks of gestation were more likely to be hospitalized for bronchiolitis than infants born after 37 weeks gestation. The influence of PM2.5 on bronchiolitis risk was stronger during the winter months. Understanding the role of PM2.5 in terms of increased susceptibility to illness is important for adopting preventive measures. This work can provide evidence to support regulations when determining safe levels of PM2.5 for infants.
Co-author: David Lyon (lab director and advisor)
Determining the detailed microcircuitry of connections in the brain is a critical step toward understanding the functional mechanisms in healthy and diseased tissue. By studying the cortical projections in an animal model, we can begin to define the complex pathways that are involved in human cognition. Additionally, we can develop techniques to visualize these pathways and ultimately create a map of the cortical projections, which in turn can facilitate the management and treatment of a myriad of neurological conditions. The goal of our project is to characterize one such pathway (hypothalamus to visual cortex).
The primary visual cortex (V1) is the region of cortical neurons that start to interpret sensory inputs from the retina. Previous studies have suggested an inhibitory role of projections from the lateral hypothalamus to the visual cortex in the monkey, but no additional work has been done to characterize this connection or demonstrate its presence in other animal models. Our preliminary results show a direct input to V1 from the lateral hypothalamus in the mouse, specifically the lateral preoptic area. This region has been implicated in thermoregulation and sleep cycles in rats, as well as osmosensitivity and thirst-regulation. Characterization of this projection may shed light on appetite and sleep stimulation that may contribute to our understanding of homeostatic regulations.
Our research will examine the subcortical-cortical links using retrograde labeling from a targeted rabies virus injected into V1. In combination with specially designed helper viruses, modifications to the rabies virus limit initial infection to inhibitory or excitatory neurons and retrograde spread only to presynaptically connected neurons. The rabies expresses a red fluorescent reporter, allowing cell bodies, dendrites, and axons of all connected cells to be identified clearly in their place of origin. We will determine which specific subregions contain these labeled cell bodies to identify additional subcortical projections to V1. This will help to identify candidate behaviors that may be regulated by the pathway. Key to the tracing strategy are the different helper viruses that will be utilized to determine the inhibitory or excitatory nature of the pathway. Since the brain consists primarily of excitatory neurons, the ability to independently target inputs to excitatory or inhibitory V1 neurons will allow us to better determine whether this pathway plays a role in inhibition as predicted by earlier work. Such interactions with inhibitory neurons could serve an important modulatory role on basic visual processes and visually related behaviors.
Genetically isolated populations have higher prevalence of a variety of genetic diseases. In Israel in the Ashkenazi Jewish population specifically we see that the burden of rare genetic diseases is heavy. 20 years ago Israel introduced a program of comprehensive premarital and prenatal screening, resulting in reduction of genetic diseases like Tay-Sachs. Prevention of these rare disease variants is dependent upon couples that are both carriers of a disease allele choosing not to have children, or selectively aborting fetuses that carry both mutant alleles for a rare disease. While these methods have been effective in reducing the prevalence of cases it has not addressed the fixation of these alleles in the population nor has it addressed the health impact of selective abortion. Current technology provides genetically isolated populations the potential opportunity to apply additional screening to reduce the prevalence of rare disease cases and also increase the speed at which a mutant allele is fixated. All, without necessitating an intervention which challenges mothers health and negatively impacts a woman’s reproductive lifespan.
Online dating is a method of courtship that is gaining popularity. In the genetically isolated country of Israel, approximately 20% of the unmarried adult population has pursued courtship using online dating sites. Genetic screening tools are beginning to be offered along with dating services. Testing the potential impact of these screening applications can be accomplished through time forward population simulation.
Methods: A time forward population simulation model was used for this study. Simulation used published prevalence of Gaucher disease carriers to create simulated populations. Simulation was used to identify the impact of such an application assuming different size of user base, fitness of carriers, online dating success rate, increasing rates of admixture, screening error rate, and proportion of population using traditional dating and screening, on rare disease prevalence.
Results: Without Online dating intervention, carrier frequency decreased by .002-.004% per generation. Assuming 50% of the dating populous enrolled and 50 % achieved successful courtship then carrier frequency would decrease by .004-.005% per generation.
Conclusion: Current screening methods can be enhanced by genetic screening via online dating. However, it is a large assumption that the proportion of online daters will increase by 50% and 50% of those daters will successfully complete their courtship. Nevertheless this study is the first to highlight the potential impact of a new genetic screening tool.
Substance abuse costs the US economy half a trillion dollars annually due to crime, lost work productivity and healthcare. As well as draining resources from the economy, substance abuse inflicts an exorbitant toll on the lives of millions of Americans. Drug addiction is a particularly persistent disease given that only 10% of addicts remain drug abstinent 6 months after completing drug rehabilitation. Drug addiction is characterized in part by the strong associations that are formed between the environment and the rewarding properties of the drugs. These drug associations increase in strength over the course of drug abuse. Eventually, these associations become so resilient that after months or years of abstinence, drug-associated memories are capable of driving drug cravings and ultimately relapse. My research seeks to understand the molecular mechanisms involved in the acquisition of drug-associated memories with the goal of diminishing the strength of these memories.
Long-term memory formation is known to require gene expression. In the last two decades, the role of gene expression in addiction has led researchers to focus on the epigenetic mechanisms that regulate gene expression. Epigenetics commonly refers to mechanisms that regulate gene expression by altering chromatin structure, independent of changes in DNA sequence. Marcelo Wood’s lab, here at UCI, has shown that epigenetic mechanisms play an integral role in regulating gene expression necessary for the formation and extinction of cocaine-associated memories and cocaine-induced behaviors. However, there is a major epigenetic mechanism, chromatin remodeling, which is capable of generating changes in gene expression but up until now has not been studied in the field of drug addiction. Throughout the course of my research, I use two selective genetic manipulations to target and disrupt a key component (BAF53b) of a chromatin remodeling complex (nBAF) then examine the subsequent effect on cocaine-associated memories and behaviors. Our lab generated genetically modified mice that have reduced BAF53b or a non-functioning form of BAF53b. These mice were then given cocaine in a distinct environment and their memory for that event was later tested. My research demonstrates that both genetically modified mice have deficits in cocaine-associated memories but not all cocaine-induced behaviors. These results show for the first time that chromatin remodeling plays a role in the formation of cocaine-associate memories. In addition, these results possibly provide a novel target for therapeutics aimed at combating addictive disorders.