Robin Harris - US grants

Southern Arizona has among the highest skin cancer rates in the world and the Arizona Cancer Center has an active and unique registry for identification of all skin cancers diagnosed within three southeastern counties of the state. Little is known, however, about the role genetic risk factors have in the etiology of cutaneous melanoma within this region and how genetics and environment, most particularly high ultraviolet exposures, interact. The primary objective of this project is to develop and evaluate a system to routinely identify the family history of newly diagnosed melanoma patients and develop a repository of genetic information for melanoma cases in a defined population. This project proposed to develop the resources and experiences needed prior to proposing a more complex genetic epidemiologic investigation in Arizona of cutaneous malignant melanoma. This two year project proposes to incorporate the collection of family history data for all cutaneous malignant melanoma cases identified by the Southeastern Arizona Skin Cancer Registry. This routine assessment would allow identification from a defined geographic population of potential melanoma families with more than one first-degree relative with melanoma. These cases and families could then be available for recruitment into subsequent, focused genetic studies. We propose to also collect and analyze samples for mutational analyses of the p16INK4/CDK2N gene in a series of select kindreds.

The overall goals of this proposal are to examine geographical variation in the association between cancer risk and potential environmental exposures, in particular arsenic exposure, and to then determine the homogeneity of the associations as the geographical scale changes. Uses of Geographic Information Systems (GIS) have made it more feasible to link multiple sources of descriptive attribute information for various geographic levels with health outcome data. The use of GIS allows the spatial relationships between the data elements to maintained and analyzed. Arsenic exposure may be a causal agent in the development of bladder, lung, kidney, and skin cancers. Furthermore, arsenic is known to vary across geographical locations. Several geographically delineated data sets exist in the State of Arizona that allow for epidemiological exploration of the relationship between arsenic exposure and cancer occurrence. Geocoded cancer incidence and mortality data are available from the Arizona Cancer Registry for bladder, kidney, and lung cancer. Skin cancer data are available from a completed population-based case control study. Arsenic concentrations are available from a multimedia, multipathway survey conducted in Arizona. The specific aims for this proposed research are 1) to evaluate spatial scales and determine relationships between the scale used by the Atlas of Cancer Mortality and scales potentially more useful within the state and 2) to evaluate the relationships between the various cancers and arsenic exposure for the various geographical scales. This proposal presents a cohesive research team that encompasses faculty and staff from various colleges within the University of Arizona and state health agencies and will utilize archival data collected by various state agencies and completed epidemiological studies of skin cancer and environmental exposures.

The overall goals of this proposal are to examine geographical variation in the association between cancer risk and potential environmental exposures, in particular arsenic exposure, and to then determine the homogeneity of the associations as the geographical scale changes. Uses of Geographic Information Systems (GIS) have made it more feasible to link multiple sources of descriptive attribute information for various geographic levels with health outcome data. The use of GIS allows the spatial relationships between the data elements to maintained and analyzed. Arsenic exposure may be a causal agent in the development of bladder, lung, kidney, and skin cancers. Furthermore, arsenic is known to vary across geographical locations. Several geographically delineated data sets exist in the State of Arizona that allow for epidemiological exploration of the relationship between arsenic exposure and cancer occurrence. Geocoded cancer incidence and mortality data are available from the Arizona Cancer Registry for bladder, kidney, and lung cancer. Skin cancer data are available from a completed population-based case control study. Arsenic concentrations are available from a multimedia, multipathway survey conducted in Arizona. The specific aims for this proposed research are 1) to evaluate spatial scales and determine relationships between the scale used by the Atlas of Cancer Mortality and scales potentially more useful within the state and 2) to evaluate the relationships between the various cancers and arsenic exposure for the various geographical scales. This proposal presents a cohesive research team that encompasses faculty and staff from various colleges within the University of Arizona and state health agencies and will utilize archival data collected by various state agencies and completed epidemiological studies of skin cancer and environmental exposures.

The overall goal of this project, Cumulative Environmental Effects: Expanding Research with the Hopi Tribe, is to use a community-based participatory research (CBPR) approach to collaborate with the Hopi Tribe investigating household exposures to inform policy decisions. Household exposures are major sources of environmental hazards encountered by many American Indian and Alaska Native (AI/AN) communities. Household exposures include combustion by-products from heating and cooking, particulate from nearby mining and other land uses, and water and food contamination. These exposures, and co-exposures such as unemployment and poor access to preventive programs and health services, impact respiratory health and obesity among children and adults, and warrant evaluation of AI/AN household exposures within a social ecological framework. The Hopi Tribe in northern Arizona has identified several areas of concern, including the impact of burning coal and biomass in homes for heating and its potential impact on respiratory health. Other issues include concerns about arsenic and uranium species in drinking and surface water. Arsenic exposure is linked to compromised lung function and an increase in body mass index. This application seeks to expand existing relationships to include Hopi officials in the Hopi Environmental Protection Office and university environmental scientists and health promotion experts. The project proposes to: 1) Characterize magnitude of environmental exposures to particulate matter (PM), arsenic species, uranium and other contaminants from air, water, and food in selected households on Hopi tribal lands; 2) Evaluate how exposures are moderated by social determinants of health, social capital, community resilience and other cultural assets; and 3) Expand Hopi capacity to address areas of environmental concern. The effort will build additional capacity within the Hopi Tribe to evaluate and mitigate environmental hazards of concern to the Tribe. The proposed joint project provides an opportunity to develop and strengthen a relationship built on trust between the Hopi Tribe and university researchers and to increase the capacity of the Hopi Environmental Protection Office to monitor its air and water quality. Anticipated results include modeling of cumulative exposures to arsenic species and particulate among Hopi residents and addressing environmental concerns of the Tribe in terms of health inequities. The project will build the Hopi Tribe's capacity to conduct research on adverse exposures and develop programs that inform tribal environmental and health policies for a sustainable future.

PROJECT SUMMARY/ABSTRACT This proposal is a resubmission of the University of Arizona Cancer Center?s (UACC) Cancer Prevention and Control R25T postdoctoral training program re-competition. This program was first funded by the National Cancer Institute (NCI) in 1998 as a R25T and currently continues under that mechanism (2R25CA078447). Our R25T program is currently in a no cost extension year and has supported 9 successful postdoctoral fellows over the current grant cycle (2010 ? 2015), 44% of whom are from underserved populations. This T32 proposal requests 4 postdoctoral positions per year for two-year training periods with the goal to train a maximum of 10 postdoctoral trainees over five years. Upon program completion, T32 fellows will be prepared to proceed to successful and productive independent cancer health disparity research careers that contribute to decreases in cancer morbidity and mortality among underserved populations. This will be achieved through two designated foci: 1) recruit qualified trainees committed to cancer prevention work in underserved populations, including researchers from underserved communities and those with an interest in cancer health disparities science; and 2) train individuals in cancer prevention and control and health disparities science to reduce health disparities. During this training program, fellows will be required to 1) engage in a primary research project along with required coursework, including a health disparities training curriculum; 2) attend and lecture in the weekly UACC Cancer Prevention and Control seminar series; 3) submit their work for presentation and publication in peer-reviewed journals; 4) attend scientific and career development meetings; and 5) develop a grant proposal for research funding. This proposed Cancer Prevention and Control Health Disparities Training Program aligns with the University of Arizona?s strategic plan and addresses the needs of our State?s unique population (25.5% Hispanic, 4.1% African-American, and 5.8% Native American residents, as compared to national averages of 15.8% Hispanic/Latino, 12.6% African-American, and 0.7% Native American (US Census Bureau)). This distinctive geographic location along with our strong community ties, university partnerships, CPC postdoctoral training history, and university infrastructure and resources uniquely position us to train the next generation of CPC researchers focused on reducing health disparities and working with underserved communities.

PROJECT SUMMARY/ABSTRACT: PROJECT 3 HELICOBACTER PYLORI AND STOMACH CANCER AMONG NATIVE AMERICAN POPULATIONS Helicobacter pylori (Hp) is a common gastric pathogen that is associated with the development of duodenal or stomach ulcers, stomach cancer, and mucosa associated lymphoid-tissue (MALT) lymphomas. While the overall incidence of gastric cancer has declined over time in the United States (US), there are clear racial and socioeconomic health disparities in gastric cancer rates and associated outcomes. This translational, multi- method project seeks to better understand the role of Hp infection in the development of stomach cancer among Native Americans (NA) of Northern Arizona where stomach cancer incidence rates are approximately three times as high compared to the general Arizona population and it is the leading cause of cancer-related mortality. Despite this high burden, social, environmental, and pathogen-associated risk factors remain unknown for this underserved population. While prevalence varies within populations, Hp prevalence within Navajo Nation is likely high. Our pilot study of 72 households found 59% of 108 participants were Hp positive by urea breath test (UBT) and 74% of households had at least one person positive. Furthermore, prior knowledge of Hp and its link to stomach cancer is low in these communities. However, 53% of Hp+ cases did seek care at the local urban Indian Health Service facility, indicating concern. Risk factors for Hp infection in this distinct population are not clearly defined nor are barriers to receiving diagnosis and treatment, precluding appropriate primary and secondary prevention strategies. Thus Aim 1 is a community-based study to identify factors associated with infection and barriers to self-referral to clinic. Since Hp subtypes may contribute to progression from infection to cancer and the prevalence of specific genotypes are unknown in this population, Aim 2 will focus on the distribution of Hp subtypes in the Navajo community members referred to clinic for endoscopy. The relationship between Hp infection and subsequent stomach cancer is related also to host immune response. Intestinal metaplasia and Spasmolytic Polypeptide-expressing metaplasia (SPEM) are histologic changes that presage gastric cancer development. SPEM is more intensively studied in mice than humans because it can be induced experimentally after introducing Helicobacter. Epithelial expression of the sonic hedgehog (Shh) ligand and mesenchymal activation of canonical Hedgehog signaling play essential roles in gastric homeostasis and recruitment of inflammatory cells. Our earlier studies found a subset of immune cells recruited to the gastric epithelium during infection become myeloid-derived suppressor cells (MDSCs), and this coincides with parietal cell atrophy and SPEM. Schlafens (SLFN) are a family of molecules strongly induced by type 1 interferons that correlate with immune cell quiescence. Using whole genome analysis of mouse cells, we identified a microRNA signature for this IFN-regulated immune cell in both metaplastic gastric tissue and serum of both infected mice and humans. Thus, in Aim 3 a miRNA signature will be analyzed in the gastric biopsies and compared to its presence in serum collected at time of endoscopy.

One of the properties of life is the ability to detect and respond to environmental stimuli, which is facilitated in animals by sophisticated sensory systems such as vision, audition, and olfaction. However, compared to vision and audition, large gaps exist in our understanding of olfactory space and the evolution of odor discrimination. This project investigates the interplay between odors and their specific receptors by using ants as a new olfactory model system to help decipher the olfactory code. Ants depend on their olfactory sense to communicate with each other and to differentiate between colony members or non-members. For this purpose, they use chemicals that occur on their body surface and that provide a large vocabulary of chemical ?words?. Their importance in ants is reflected in the large repertoire of olfactory receptors that are sensitive to these compounds. Discrimination bioassays, analyses of olfactory receptor tuning to these compounds, analyses of receptor evolution and a structure/function analysis of the olfactory receptors will decipher how discrimination of compounds can be improved at the receptor level. The outcome of this research will help fill a gap in our fundamental understanding of olfaction and communication through olfaction. The project will be used to train undergraduate and graduate students as well as high-school students from underrepresented groups in modern approaches of behavioral analysis and experimentation. An educational game about olfactory discrimination will be produced that can be integrated into classroom lessons for high school students.

Understanding the mechanisms of odorant discrimination is still a challenging problem in the sensory physiology of animal behavior that includes the receptor level and the processing of olfactory information in higher brain centers. This project focuses on mechanisms of odorant discrimination at the receptor level and uses the compound group of cuticular hydrocarbons for this purpose. Cuticular hydrocarbons occur as complex mixtures of long-chain hydrocarbons on the body surface of almost all insects and are used in many important contexts, including mate communication and colony discrimination, which require classification of individuals based on their cuticular hydrocarbon profiles. In social insects, discrimination against non-colony members is especially important to avoid any form of colony exploitation. Therefore, strong selection on these discrimination abilities is expected in social insects. The rich olfactory receptor repertoire in ants will be exploited to identify key receptors in the discrimination of cuticular hydrocarbons. Tuning curves of these hydrocarbon sensitive olfactory receptors will be determined and compared. These analyses will be combined with bioassays to determine differences in the discrimination of individual hydrocarbon compounds. The abundance of cuticular hydrocarbon sensitive olfactory receptors in the receptor phylogeny of ants, and the presence of many closely related olfactory receptors following gene duplications, provide the foundation of structure/function analyses. The combination of functional analyses of ligand specificity of closely related olfactory receptors with the three-dimensional reconstruction of the receptor molecules will establish how molecular sequence changes lead to the expansion of olfactory space.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PROJECT SUMMARY Cell death has a critical role in wound healing and regeneration following injury, disease or infection. Apoptosis at a site of injury can significantly impact the behavior of surrounding cells, as signals produced by dying cells can induce inflammation, proliferation and dictate the survival of their neighbors. These activities can therefore directly regulate a tissue?s ability to recover from damage. For example, following liver injury in mice, signaling molecules produced by dying hepatocytes drive regenerative proliferation. Thus, a better understanding of how a tissue responds to damage-signals could uncover novel therapeutic interventions to improve wound healing and regeneration. Although advances have been made in understanding how apoptosis contributes to regeneration, little is known about whether non-apoptotic forms of cell death, such as necrosis, might have a similar role. Necrosis occurs in numerous human diseases, particularly following ischemic injury (stroke and heart attack), infections and cancer. Regeneration following necrotic cell death is significantly more variable than that induced by apoptosis, but has been documented in various tissues, suggesting that as yet unidentified and distinct mechanisms might exist in each context. Thus, the aim of this work is to characterize the fundamental genetic mechanisms that lead to regeneration following necrosis versus apoptosis. Evidence that signals from apoptotic cells impact surrounding tissues first originated from studies of the larval wing primordia in Drosophila, an attractive and powerful model to study regeneration. The genetic tools available in Drosophila have led to important insights into the genetic events necessary for regeneration. Studies of regeneration in the larval wing commonly rely on genetic ablation, an efficient and robust approach that permits spatially and temporally controlled cell death to be induced in tissues. However, despite its advantages, this method is also limited in the genetic manipulations that can be achieved, and is lacking the ability to study non- apoptotic forms of tissue loss, such as necrosis. To overcome these problems we have established a new method, DUAL Control, that allows us to induce necrosis or apoptosis in the developing wing primordia, stimulating a regenerative response to either type of damage. Our initial investigations suggest that necrosis and apoptosis lead to dramatically different gene expression changes and morphologies in the surrounding tissue. Importantly, however, regeneration occurs in both situations. As an advance on previous approaches, this novel system also allows us to target genetic manipulations specifically to the surrounding regenerating tissue, independent of ablation. These experiments can therefore take advantage of the large purpose-built RNAi screening libraries available in Drosophila to interrogate regenerating cells directly. We propose to use this new method to characterize the genetic response to damage that leads to successful regeneration following necrosis compared to apoptosis, with a view to identifying novel regulators of regenerative capacity in each context.