insulin like growth factor i

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..In this review, many aspects of the IGF system and its relationship to cancer will be discussed...

..Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling...

..The preservation of muscle architecture and age-independent regenerative capacity through localized mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty...

..Recent results are encouraging and have justified the expansion of many translational research programmes...

..Thus, strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab...

..This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required...

..The regulation of cell sensitivity to inhibitory IGFBP signaling may play a role in the growth control of malignant cells...

..Thus, these data suggest that the signal interaction between IGF-1R and alpha(v)beta3 integrin plays an important role in promoting the development and progression of cervical cancer...

..Finally, the -/- mice lived significantly longer than +/+ and +/- mice. The latter result contradicts the anti-aging GH data and suggests the need for further analysis of GH and aging...

..Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years...

..This is the first mechanistic study demonstrating that IGF-I supplementation abrogates the protective effect of DR on neoplastic progression...

..Thus, it appears that signaling from the IGF-I receptor utilizes two distinct pathways leading either to proliferation or differentiation...

..These findings demonstrate for the first time the ability of insulin and IGF-1 to activate the beta-catenin pathway in hepatoma cells and thereby provide new insights into the role of these factors in hepatocarcinogenesis...

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..Downregulation of the IGF-1R leads to massive apoptosis of cancer cells. These characteristics make it an attractive target for anticancer therapy...

..Involvement of the MAP kinase pathway represents a novel mechanism for the induction of HIF-1 alpha protein expression in human cancer cells...

..We suggest that this network of tissue interactions and feedback regulation allows the tissues to equilibrate and fine-tune their expression of downstream genes, which, in turn, coordinates their rates of aging within the animal...

..We report that insulin-like growth factor 1 prolongs life and delays disease progression, even when delivered at the time of overt disease symptoms...

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..Circulating concentrations of IGF-I might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk...

..For cancers of the endometrium, breast and prostate, these findings are discussed in the context of relationships between insulin and IGF-I and levels of bioavailable sex steroids...

..To test this hypothesis, we conducted a case-control study nested within a cohort of 14 275 women in New York...

..The phenotypic manifestations of the mutation were correlated with the localization of transcripts for insulin-like growth factor I and its cognate receptor in wild type reproductive tissues by in situ hybridization...

..The roles of the IGFs in mouse embryonic development, as revealed from the phenotypic differences between these mutants, are discussed...

..These data implicate mIGF-1 as a powerful enhancer of the regeneration response, mediating the recruitment of bone marrow cells to sites of tissue damage and augmenting local repair mechanisms...

..Our goal was to determine whether an association exists between serum levels of IGF-1 and one of its binding proteins, insulin-like growth factor-binding protein 3 (IGFBP-3), and prostate cancer risk...

..Histopathology is characterized by underdevelopment of muscle tissue. Lungs of late embryonic and neonates also appeared less organized with ill-defined alveolae. IGF-I appears to be essential for correct embryonic development in mice...

..They also had resistance to the glucose-lowering effects of insulin, IGF-1 and IGF-2. These data suggest the existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs...

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..elegans TGF-beta Dauer pathway is responsible solely for the regulation of dauer formation, with no role in longevity regulation, whereas the insulin/IGF-1 signaling (IIS) pathway regulates both dauer formation and longevity...

..The decrease in the cyclin D1 content in conjunction with the inhibition of nestin expression by ERK inhibitor confirms the role of ERK in the proliferation of cells...

..Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation...

..Thus, we conclude that KCC activation by IGF-1 plays an important role in IGF-1 receptor signaling to promote growth and spread of breast cancer cells...

..Taken together, our results suggest a critical role for IGF-1 and the IRS/PI3K/Akt pathway in the process of membrane assembly at the axonal growth cone...

..This study investigated whether rehabilitative exercise training decreases the levels of systemic or local muscle inflammation or reverses the abnormalities associated with muscle deconditioning...

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..The aim of this study was to illustrate the present role of transsphenoidal surgery as primary therapy in GH-secreting adenomas, and to compare the results concerning control of disease with previous series using older criteria of cure...

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..These analyses indicate that high levels of circulating IGF-1 and particularly low levels of IGFBP-3 are associated independently with an elevated risk of large or tubulovillous/villous colorectal adenoma and cancer...

..Finally, life span was significantly extended for the GHR -/- mice but remained unchanged for GHA dwarfs. These results suggest that the degree of blockade of GH signaling can lead to dramatically different phenotypes...

..They also explain why diabetic retinopathy initially increases with the onset of insulin treatment. IGF-1 levels, low in untreated diabetes, rise with insulin therapy, permitting VEGF-induced retinopathy...

..Upon stimulation of cells by IGF-I, GRC translocates to the plasma membrane. Thus, IGF-I augments calcium entry through GRC by regulating trafficking of the channel...

..The aim of the present study was to clarify the relationship between GH deficiency (GHD) and some cardiovascular risk factors and to analyse the effect of GH replacement therapy in a large number of patients over a prolonged period of time...

..For example, excess growth hormone causes insulin resistance and hyperglycemia, whereas IGF1 has insulin-like effects that reduce blood glucose levels and has been used experimentally to treat both type 1 and type 2 diabetes...

..This mechanism may explain why IL-6 is a strong risk factor for disability...

..In turn these pathways regulate cell growth, proliferation, and death. These networks are central to our understanding of a variety of physiological and pathological conditions, including cancer, diabetes, and longevity...

..Our results indicate that by targeting a growth factor-mediated survival signaling pathway, BAD phosphorylation can be manipulated therapeutically to induce apoptosis...

..These findings suggest that IGF-I is a key factor in the regulation of NSC activation and that EGF and FGF-2 control striatal NSC proliferation, in part, through distinct intracellular mechanisms...

..Aim of this study was to evaluate the diagnostic cut-off limits of peak GH response to the GHRH-ARG test in overweight and obese as well as in lean population...

..Our results demonstrate the power of transcriptional profiling for gene discovery and provide opportunities for investigating new proteins potentially involved in different aspects of growth factor action in muscle...

..This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms...

..The ARG plus GHRH test represents an excellent alternative to the ITT for the diagnosis of GH deficiency in adults...

..Taken together, these data reveal that the survival properties of both IGF-1 and BDNF against serum deprivation are mediated by the activation of the PI3K/Akt, but not the MAPK, pathway in hippocampal neurons...

..A comparably high degree of amino acid sequence identity is also found for both the amino- and carboxyl-terminal extension peptides, suggesting that, like mature IGF-I, the extension molecules may have physiological function...

..Together, the data provide clear evidence that SOCS2 is a negative regulator of GH signaling...

..These results suggest that therapeutic growth factor gene delivery using encapsulated and transplanted genetically modified chondrocytes may be applicable to sites of focal articular cartilage damage...

..Here we report for the first time that IGF-1 infusion decreased atherosclerotic plaque progression in ApoE-deficient mice on a Western diet...

..This association was independent of baseline prostate-specific antigen levels. Identification of plasma IGF-I as a predictor of prostate cancer risk may have implications for risk reduction and treatment...

..Later splicing of the IGF-I gene away from MGF but towards IGF-IEa seems physiologically appropriate as IGF-IEa is the main source of mature IGF-I for upregulation of protein synthesis required to complete the repair...

..This phenomenon may explain the efficacy of IGF-I as an inhibitor of apoptosis in many different cell types and in the presence of different apoptogenic stimuli...

..However, their high antioxidant capacity may result in lower oxidative damage. Enhanced molecular turnover rates may also play a role in their longevity phenotype...

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..5th centile. In conclusion, the automated IMMULITE IGF-I and IGFBP-3 assays are reliable tools in the diagnosis of pathologies of the GH/IGF axis and in the follow-up of their therapies...

..The robust response achieved with the mIGF-1 isoform provides a mechanistic basis for clinically feasible therapeutic strategies for improving the outcome of heart disease...

..A meta-analysis of mortality studies in acromegaly has thus been performed to assess the effect of lowering serum GH and IGF-I on survival...

..Our results suggest that, by interfering with Akt activation, TRB3 contributes to insulin resistance in individuals with susceptibility to type II diabetes...

..Our results suggest that loss of the ability of IGF-I to activate Shc signaling to MAPK may be an early component of adipogenesis in 3T3-L1 cells...

..Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells...

..Insulin-like growth factor 1 (IGF-1) has antiapoptotic and mitogenic effects on various cell types, and raised IGF-1 levels are increasingly being implicated as potential risk factors for cancer...

..These mice offer an animal model for prostate cancer that will allow study of the stepwise development of this disease and the mechanism(s) whereby IGF-1 mediates this process...

..Surgery is the primary treatment of acromegaly. However, it often fails to cure the patient. New strategies that improve surgical outcome are needed...

..Thus, in bovine granulosa cells, metformin decreases steroidogenesis and MAPK3/MAPK1 phosphorylation through AMPK activation...

..Because IR also activates signaling pathways similar to IGF1R in breast cancer cells, agents targeting both receptors may be necessary to disrupt the malignant phenotype regulated by this growth factor system...

..These findings suggest an important, novel role for IGFBP-2 in obesity prevention...

..We conclude that targeting the IGF-IR and the PI3K pathways is a promising new strategy to treat cisplatin-resistant ovarian carcinomas...

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..We conclude that higher energy, protein, and milk intakes were associated with higher levels of IGF-I. These associations raise the possibility that diet could affect cancer risk through influencing IGF-I level...

..In conclusion, long-term continuous GH treatment in short children born SGA without signs of persistent catch-up growth leads to a normalization of AH, even with a GH dose of 3 IU/m(2).d ( approximately 0.033 mg/kg.d)...

..We conclude that the induction of cell proliferation and tumor formation by long-term IGF stimulation may primarily be due to anabolic effects, in particular increased amino acid production and uptake...

..This DAF-28 mutant is likely to be poisonous to wild-type DAF-28 and other insulins...

..Here, we critique the current mammalian models of GH/IGF-1 deficiency and discuss the actions of GH/IGF-1 on biological aging and lifespan...

..The possible clinical prevention of age-related muscle wasting (and associated motorneurone loss) by the locally acting muscle isoform of IGF-I is discussed...

..Given the emerging evidence for the role of the stroma in these processes, we aimed to characterize the effects of IGF-I on cancer cells and stromal cells separately...

..The therapeutic potential for ceramide to limit dysregulated VSMC growth has direct applicability to vascular diseases such as restenosis and atherosclerosis...

..Further family and pedigree studies are needed to characterize the relationship of bone mass acquisition to the IGF-I genotype...

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..Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan...

..The age-related decline in plasma IGF-I may be exacerbated by low intakes of protein and minerals. The potential role of these dietary factors on cancer risk through altering IGF-I levels requires study...

..These changes were either less or not found in L1. Thus, lack of IGF-I leads to the development of a bone structure, which, although smaller, appears more compact...

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..The results provide a basis for localized tissue adaptation and helps explain why loss of muscle mass occurs in the elderly and in dystrophic muscle in which MGF production is markedly affected...

..Restriction endonuclease polymorphisms in the IGF-I gene, which map near exon 5 as determined by Southern blot analysis, will be useful in defining the genetics of familial growth failure...

..IGF-1 is one of the signals underlying autonomous development of the otic vesicle...

..This finding suggests that, in addition to testosterone, IGF-1 may increase the risk of prostate cancer in humans...

..Taken together with previous data demonstrating that IGF-I promotes proliferation of peripheral macrophages, these data support the hypothesis that IGF-I is an autocrine/paracrine mitogen for microglia/macrophages after H/I...

..Thus these data suggest that the IGF1 promoter polymorphism may influence the strength response to ST. Larger sample sizes should be used in future studies to verify these results...

..The completion of the proposed experiment will allow the candidate to compete as an independent research investigator. ..

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..Cachexia is also a complication of many other conditions including lung and heart disease and aging, the knowledge generated through this proposal also will help us in establishing new therapies for these conditions. ..

..Moreover, elucidation of the signaling mechanisms that regulate autophagy in cardiomyocytes may lead to novel therapies for preventing or modulating heart injury as occurs in diabetes, cardiac ischemia or cardiac hypertrophy. ..

..An understanding of this pathway should ultimately enable better management of diabetic veterans and conceivably lead to the design a single therapy, which can simultaneously target both osteoporosis and type 2 diabetes. ..

..In addition, the enzyme activity is necessary for protection against the fatal "green jaundice". Our work has revealed a novel approach for development of therapeutic interventions in a range of human diseases. ..

..Our mouse- implantable remote-control micropump technology overcomes this limitation;enabling more rapid, efficient, and economical discovery and delivery of regenerative therapies. ..

..5. To prepare annual progress reports and coordinate preparation of a competing renewal application. ..

..We will subsequently test the optimal combination of these factors using gene delivery in a rodent model of this devastating disease in order to define an optimal therapy for this debilitating disorder. ..

..Effects of DR that extend life spans in both normal control and ob/ob mice in this study are likely targets for interventions to retard aging and extend healthy lifespan in human beings. ..

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..Information gained can be used in future experiments to determine if GH acts directly or indirectly on specific tissues/cells to mediate these effects. ..

..The development of a viable non-toxic chemoprevention strategy targeting high risk women could have a significant impact on breast cancer morbidity and mortality. ..

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..The results will assist in designing dietary supplements for chemoprevention of early stages of prostate cancer or during watchful waiting. ..

..The work in this proposal will determine if this approach is feasible using animal models of this disease state. ..

..Establishing that maternal / perinatal diet influences peak bone mass acquisition may point to diet as a modifiable risk factor for adult bone disease. ..

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..The data obtained has the potential to facilitate the translation of pre-clinical and clinical research to public health guidelines for PA directed to cancer prevention and control. ..

..In addition, when the boys reach adulthood, environmental risk factors for altered semen quality will also be explored. ..

..These studies have the potential to greatly impact the management of a complex disease which has a high mortality and, thus far, few therapeutic options which improve outcome. ..

..Therefore, the failure to accrue peak bone mass during the adolescent years represents a missed opportunity to optimize bone mass during one's life. ..

..According to the NIH report "the effect of food constituents on molecular events in the prostate is unknown". Discovery of Se- and isoflavone-regulated genes will "identify biomarkers of the consumption of key dietary components". ..

..Discovery and validation of potent antitumor action and tolerability of metformin analogs in vivo may lead to timely clinical trials and possibly a significant breakthrough in pancreatic cancer therapy. ..

..We hope to enhance innate immunity and/or reduce average lifespan of a model mosquito below this development period so that transmission of malaria parasites is reduced or eliminated. ..

..It will also shed light on ways to prevent prostate cancer recurrence that may involve new or existing medicines or lifestyle changes. ..

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..A nonhuman primate model of gestational overnutrition is a vital resource to explore the effects of weight on the health of mothers, children, and perhaps even subsequent generations. ..

..In addition, the establishment of a lung carcinogenesis model in ferrets provides a valuable tool for both lung cancer and carotenoid research fields. ..

..This proposal thus addresses important questions about how leptin can affect reproductive competence at the level of the pituitary. ..

..If effective in these patients, then this holds the potential of improving management of patients, not only with CKD, but also those with other muscle wasting illnesses. ..

..The study will be conducted in a large, prospective cohort study of endometrial cancer (GOG-0210). ..

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..Improved understanding of how different nutrients, when provided chronically in excess, alter the cell's response to insulin, will lead to the development of novel therapeutic targets to prevent or mitigate type 2 diabetes. ..

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..Thus, the genetic-molecular status of the heart may condition the outcome of aging and genetic manipulations may interfere with the development of the cardiac senescent phenotype in both genders. ..

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..Such information will be instrumental in designing preventive and therapeutic modalities to fight aging related diseases. ..

..In addition, we will use a novel statistical approach, Reduced Rank Regression (RRR), to develop diet patterns that represent the effect of diet on cancer biomarkers. ..

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..Should the positive effects of augmented exercise on body composition be supported, we would then anticipate widespread benefit in preventing long-term health consequences of prematurity at relatively low cost. ..

..Furthermore, the proposed studies will establish molecular mechanisms underlying the anticancer effects of CR, especially in the putative target cells (i.e., stem cells) for cancer development. ..

..Together, these studies will provide critical mechanistic and pre-clinical information needed to better understand how corrections in insulin and/or IGF-I in diabetes may be beneficial in preventing and treating diabetic osteopathy. ..

..These findings will allow development of innovative therapies to treat cachexia in chronic conditions in which the RAS is activated. ..

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..The results of the proposed studies will therefore be highly relevant for improving public health, and improving the length and quality of life of millions of patients with ischemic heart disease and heart failure. ..

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..The study has the potential to stimulate developments of drugs to ameliorate or prevent acquired muscle weakness. ..

..These studies will provide insight into how the brain's control of reproduction is affected by the nutrition dependent hormones insulin and insulin-like growth factor-1. ..

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..These biosensors will be designed to measure oxidized nucleosides, 8-oxodeoxyadenosine and 8-oxodeoxyguanosine, in the DNA of sperm from infertile men. ..

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..The proposal may lead to development of a novel cancer biomarker and/or a drug target. The proposal will catalyze PIs transition to non-SCORE funding mechanism and enhance biomedical research at a minority serving institution like UDC. ..

..Insulin-like growth factor-I (IGF-I) enhances cartilage repair and this grant tests long-term growth factor expression in joints where degradation is controlled by RNA interference. ..

..Results derived from the studies proposed could have significant implications for therapy of bone disorders such as hyperparathyroidism, osteoporosis and renal osteodystrophy. Thus, its relevance is high for skeletal biology. ..

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..Furthermore, the study will test the clinical usefulness of targeting Notch signaling to treat NSCLC using GSI. Finally, these experiments will elucidate the role of Notch-1 in lung tumorigenicity in vitro and in vivo. ..

..These findings should allow development of innovative therapies targeted at reducing acute vascular events that are most often related to plaque instability. ..

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..Freund has a unique opportunity to develop into an outstanding clinician and scientist. ..

..We will evaluate gene and protein expression of key components of the ubiquitin-proteasome pathway, as outlined in aim #3, as well as markers of signal transduction and outcome measures as outlines in aim #1. ..

..The findings should also contribute to the general understanding of the mechanisms by which ethanol affects the biology of many human tissues, including those of the fetus. ..

..This will permit better treatment of the human disease and improve the quality of life for patients with this common metabolic disorder...

..These studies will significantly expand knowledge of GH and cytokine signaling and of biologicallyrelevant crosstalk between cytokine and growth factor signaling systems. ..

..Specific Aim 4 will determine how IGF-1 acutely potentiates a1-adrenoceptor signaling in the HYP-POA of E2-treated females and whether this is important for reproductive behavior. ..

..In the future, this may provide the basis for guidelines for the evaluation and treatment of children with growth disorders. ..

..The team is led from by Drs. Colditz and Anderson and is supported by a senior statistician (Dr. Rosner) and a study director (Dr. Birmann) who is funded, in part, through a K award. ..

..Results of this work are expected to have a significant impact on reproductive endocrinology by providing scientific evidence to support new clinical interventions in patients with polycystic ovary syndrome. ..

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..In addition, the results will provide important information on the potential risks of administration of growth hormone and IGF-l to the elderly. ..