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Record Count: 5
To sort columns alphabetically or numerically, click on the column
header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant): Endogenous and environmental oxidation can cause DMA damage along with other organelle injury. For example, hyperoxia is a main therapeutics for acute lung failure but also causes lung cell toxicity. Since treatment of hyperoxic toxicity and other oxidation is largely supportive and natural defense mechanisms are easily defeated, development of new therapeutic strategies is warranted. Our preliminary data indicates that hyperoxia induces apoptosis associated with activation of mitogen-activated protein kinases (MARK, p38 and ERK1/2). We have also found that DNA base excision repair (BER) proteins can reverse oxidative DMA damage. However, it is unclear whether BER proteins interact with signaling proteins such as MARK. The objective of this application is to determine roles of BER in hyperoxic DNA damage and the regulatory mechanism, particularly interactions of BER proteins with MARK. Our central hypothesis is that BER proteins may regulate or interact with the MARK pathway to reverse DNA damage. Hyperoxia injured cells must either cease replication due to cell cycle arrest or replicate with a mutant form of DNA. Thus, DNA repair is urgently needed. Failure to repair the DNA damage results in genetic disintegration, apoptotic cell death, and an ultimate alveolar breakdown. MARK may help efficiently repair DNA damage, thus a critical way to reduce oxidative toxicity. The rationale is that additional knowledge of BER interacting with other signaling proteins would provide a foundation to better use BER DNA repair proteins to prevent oxidative injury. To test our hypothesis, we propose the following Specific Aims: #1 To identify hyperoxia-induced DNA lesions and alterations of MARK activity; #2 To evaluate role of BER proteins in regulating MARK activity. The significance is that regulation of BER repair and signaling proteins may be potentially useful for counteracting various oxidative damage to lung cells, including chemotherapeutics and heavy metals, such as cadmium.
Crisp Terms/Key Words: protein protein interaction, mitogen activated protein kinase, gene targeting, enzyme activity, apoptosis, DNA damage, hyperoxia, DNA binding protein, protein structure function, DNA repair, DNA replication, gene expression, enzyme mechanism, adduct, cell cycle, laboratory rat, laboratory mouse
DESCRIPTION (provided by applicant): The applicant has shown that the 3rd isoform of metallothionein (MT-3) is overexpressed in most bladder cancers and that the level of expression correlates to the grade of the tumor, being highly elevated in aggressive tumors and moderately elevated in low grade tumors and some precursor lesions. An important observation in this study was that neither MT-3 mRNA or protein was expressed in the urothelium or any other cell comprising the human bladder. These findings strongly suggest that the expression of MT-3 can be translated to provide a biomarker predictive of the early cellular alterations that progress to the development of bladder cancer. It is the applicant's hypothesis that the presence of MT-3 positive urothelial cells in the urine of patients is predictive of pre-malignant, malignant, or reoccurring malignant lesions of the urothelium. The basic science arm of this study employs the applicant's newly developed model of environmentally-induced human bladder cancer. The applicant is the first to demonstrate the direct malignant transformation of human urothelial cells with cadmium (Cd+2) or arsenic (As+3). The tumor heterotransplants generated from these transformants displayed the histology expected of transitional cell carcinoma of the bladder. In addition, tumors generated from As+3-transformed cells displayed tumors having a prominent squamous component, while those from Cd+2-transformed cells had little, or no, squamous differentiation. It is the applicant's hypothesis that these tumors will provide a platform to understand environmental influences on the development of bladder cancer and to address the fundamental problem of how chemical mixtures contribute to the development of bladder cancer. The specific aims are: To prove the hypothesis that MT-3 expression is a biomarker for bladder cancer; To prove the hypothesis that the expression of MT-3 in Cd+2- and As+3- induced bladder cancer is similar to human bladder cancer and that expression is controlled at both the transcriptional and post-transcriptional level of gene regulation; and, To test the hypothesis that As+3-induced transitional cell cancers of the bladder have a prominent squamous component and that this fundamental departure in differentiation can be used to gain knowledge regarding the interaction of mixtures that cause environmentally-induced cancer.
DESCRIPTION (provided by applicant)
Alcoholic liver disease (ALD) is one of the leading causes of death and the most prevalent drinking-related health problem in the United States. It is known that ALD pathogenesis involves hepatic lipid peroxidation. However, how endogenous lipid radicals are generated and how important they are in ALD development remains a mystery. With an innovative approach consisting of on-line liquid chromatography/electron spin resonance/mass spectrometry, preliminary results of this study have shown that in bile excretion of arachidonic acid (AA)-administered rats, altered AA-derived radical metabolites due to lipoxygenase (LOX), cyclooxygenase (COX), and non-enzymatic lipid peroxidation were closely correlated with ethanol-induced liver dysfunction. The long-term objective of this proposed study is to define the links among endogenous radicals, hepatic lipid peroxidation, and ethanol-induced liver injury, thereby determining which peroxidation pathway(s) would be more critical in ALD development or might represent therapeutic target(s) against ALD. The working hypotheses are that ethanol-induced liver injury will occur when hepatic lipid peroxidation predominantly produces F2-isoprostanes (F2-isoP; markers of free radical damage in vivo) and prostaglandin (PGFa) radicals, and that the modulation of hepatic lipid peroxidation which limits such lipid radicals can consequently prevent ALD development. These hypotheses will be tested by accomplishing the following specific aims: (1) to structurally and quantitatively profile in vivo AA-derived radical adducts in three redox forms to optimize sensitivity and reliability of radical measurement; (2) to assess the association among changes of lipid radical metabolites, alternations of COX/LOX gene expression, and ethanol-induced liver injury; and (3) to define more critical lipid peroxidation pathway(s) in ethanol-induced liver injury and ALD development. Data obtained in this study are expected to lead to the submission of a future NIH RO1 grant in which radical-mediated molecular/signal pathways that may contribute to ALD will be tested.
DESCRIPTION (provided by applicant): Project Summary/Abstract Alzheimer's disease (AD) is a complex neurodegenerative disorder for which there is presently no effective therapy. While some genetic mutations are responsible for the familial AD forms, the causative factors for the non-familial forms, which represent the majority of cases, are not known. Identification of risk factors and mechanisms by which these factors contribute to the pathology of AD may therefore aid in better understanding the disease and may ultimately lead to designing an efficient therapeutic strategy to prevent the onset or stop the progression of this devastating disorder. Our longterm objectives are to identify risk factors and mechanisms by which these factors trigger the pathogenesis of AD. Hypercholesterolemia is a potential risk factors for AD. However, the mechanisms by which high blood cholesterol levels affect the brain and increase the risk of AD are not known. The objective of this application is to determine the extent to which cholesterol-enriched diets cause cellular damage in the brain with AD features. We will be using a long-term cholesterol-enriched diet in the rabbits a model system that we have found to demonstrate iron deposition, ?-amyloid (A?) accumulation, and oxidative stress, all hallmarks of AD. Our hypothesis is that cholesterol diets increase levels of the cholesterol metabolite, 27-hydroxy-cholesterol, which crosses a disrupted blood brain barrier (BBB) and activates the endoplasmic reticulum stress response, thereby activating the growth arrest-and DNA damage-inducible gene 153 (gadd153) and the cytokine, TNF-?. While activation of gadd153 triggers the generation of reactive oxygen species and the overproduction of A?, the activation of TNF-? alters iron metabolism, induces apoptosis and exacerbates oxidative stress. To test our hypothesis, our specific aims are as follows: Aim I. Identify mechanisms that underlie hypercholesterolemia-induced oxidative stress, A? accumulation and iron dyshomeostasis. We will determine the role of gadd153 and TNF-? in iron dyshomeostasis, oxidative stress induction and A? accumulation. Aim II. Determine the extent to which chelation of iron protects against the deleterious effects of hypercholesterolemia. We will determine the effect of the iron chelator, deferiprone, on hypercholesterolemia-induced iron dyshomeostasis, oxidative stress and A? generation. Aim III. Determine the extent to which lowering blood cholesterol levels reduces the entrance of 27- hydroxycholesterol into the brain, thereby inhibiting oxidative stress, iron dyshomeostasis, and A? accumulation. We will compare the effects of pravastatin (a hydrophilic statin that has a low propensity to cross the BBB) and simvastatin (a lipophilic statin that readily cross the BBB) on oxidative stress, iron dyshomeostasis, and A? accumulation. Successful completion of the present proposal may reveal the missing link between high blood cholesterol levels and AD-like pathology in the brain. PUBLIC HEALTH RELEVANCE: Project narrative Hypercholesterolemia is a serious health issue in the U.S.A. which, in addition to cardiovascular problems, may also increase the risk for Alzheimer's disease. However, the mechanisms by which high blood cholesterol levels cause AD pathology are not known. The outcome of this proposal may aid in a better understanding of the mechanisms by which high cholesterol levels in blood cause degeneration characteristic of AD, and may ultimately help in designing strategies that prevent or slow the progression of hypercholesterolemia-related forms of this devastating neurodegenerative disorder.
DESCRIPTION (provided by applicant)
The University of North Dakota STEER is designed to support undergraduate training in the environmental health sciences within the University of North Dakota. The STEER training program will expand and compliment the ongoing NIH IDeA INBRE program that is focused on fostering undergraduate biomedical research at the State's primarily undergraduate institutions and the enhancement of the undergraduate pipeline to the health professional schools. The North Dakota INBRE is focused on "Health and the Environment". The present application is targeted at filling an important gap in undergraduate training in the environmental sciences not provided by the North Dakota INBRE program. This gap is the support of undergraduate environmental science training for undergraduate students at the INBRE host research-intensive institution, the University of North Dakota. The present application will use the INBRE foundation to initiate a strong undergraduate training program in environmental health science at the University of North Dakota. The research theme will be to advance the hypothesis that environmental agents which elicit human disease cause cellular alterations in cell structure and function that can be identified as predictive biomarkers of disease development and progression. To advance this theme, the students will be involved in research that studies the role of the environmental pollutants, arsenic and cadmium, in the development and progression of human bladder, breast, prostate, and renal disease. The aims of the program are: to provide an undergraduate research experience in environmental sciences to undergraduate students at the University of North Dakota; to provide an introduction to environmental health sciences to undergraduate students at the University of North Dakota; and, to use infrastructure developed in the INBRE program to support STEER programmatic efforts and vice versa over the life of the award mechanisms.
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