Background: Despite the official acceptance of Gulf War Illness (GWI), the challenge is to provide a solid scientific explanation regarding the multitude of symptoms and diverse causes displayed in this disease. Currently, we are developing a new concept to explain phenotypic diversity and the role of diverse causative factors in complex diseases. The generally accepted concept has been that common diseases are caused by common genetic loci or are a result of common causes. Increasing evidence points to a new explanation for the causes of common diseases, such as Autism and Schizophrenia, as each of these distinct causes are real and are very diverse, as are their phenotypes. This situation could well be applied to GWI. Additionally, if the genome system is unstable, there could be a variety of symptoms, as many biological pathways could be stochastically impacted, leading to patients displaying different symptoms. Thus, a new approach is necessary to study GWI, as clearly, diverse disease conditions can be influenced by varying war conditions with the environment playing an important role in this complex disease. Objective/Hypothesis: The objective of this proposal is to determine whether there is a link between genomic instability (reflected as elevated frequencies of NCCAs) and GWI. This will be achieved by analyzing patient samples and in vitro systems that mimic the system stability under the influence of diverse factors. The central hypothesis of this proposal is that patients with GWI (or unstable cell lines) will display high levels of genome instability, particularly when challenged by various toxic agents, which can be stochastically linked to various molecular pathways and is the potential basis for diverse clinical symptoms that are seen in GWI. Specific Aims: 1) Establish a method to determine levels of genome variation/NCCAs in blood cells (lymphocytes) to monitor overall genetic instability in patients with GWI. 2) Link high levels of genome instability to various gene level alterations or molecular pathways illustrated by gene expression studies and copy number variation analysis. 3) Link varying types of adverse exposure to levels of genomic instability and diverse genetic alterations at the gene level using an in vitro system. Study Design: NCCA levels determined by SKY analysis (based on chromosomes prepared from patients blood samples) will be examined from previously identified GWI patients and control patients. GWI patient clinical information regarding status of disease will be analyzed with the help of physicians and a biostatistician. We anticipate that the increased level of NCCAs will be a reliable index of genomic instability in GWI patients. The gene expression profiles of patients will be performed to link diverse pathways to overall genome instability. Finally, an in vitro system will be used to link the status of the genome (stable or unstable) to various diverse molecular pathways (gene expression profiles) and then to different chemical treatments as possible causes of GWI identified in the Gulf War. Innovation: This proposal represents a highly innovative project both from a conceptual and technical point of view. Linking genome instability to GWI, and linking the overall genome instability to diverse molecular pathways as well as diverse causative factors is significant to understand the causative basis of GWI. In addition, using frequencies of NCCAs to measure the genome instability of GWI patients, as well as applying new types of chromosome aberrations in an analysis represent innovative aspects of this proposal. Impact: The anticipated results could potentially solve the key issue of the basis of GWI, and establish new clinical uses to establish the physical presence of GWI and the relationship to adverse exposures. This study could also potentially result in methodologies that can be used to diagnose GWI. The link between the disease condition and war-specific exposures could also be useful in prevention. From a basic medical science point of view, the successful demonstration that GWI is a complex disease that displays both diverse phenotypes and diverse causative factors will also promote similar studies on other types of common and complex diseases.
Posted on: Wed, 26 Feb 2014 23:19:09 +0000
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