The primary objective of this contract is to provide for the conduct of an epidemiologic study of the risk of breast cancer among women, ages 40- 64, in relation to oral contraceptive use. Five Field Centers shall participate in the conduct of a multicenter, population-based, concurrent case-control study to elucidate effects of : 1) current and lifetime OC use; 2) timing of OC use relative to other reproductive events; 3) differential effects of contraceptive estrogens and progestins; and 4) possible modification of OC effects by subsequent estrogen or hormone replacement therapy on the risk of breast cancer. A sufficient number of breast cancer cases and controls shall be enlisted to provide for the detection of a small overall relative risk of breast cancer (approximately a 20% increase or decrease) in oral contraceptive users compared to non-users. In addition, the sample size shall be large enough to provide for subgroup analyses, based on possible differences in risk that may exist for various subgroups. Subgroups shall be defined in terms of race, family history of breast cancer, parity and other reproductive characteristics of women, and other suspected breast cancer risk factors. A secondary objective of this contract is to examine biological differences between cases, which may be associated with exogenous hormone use. GRANT-R01HL49278 The importance of alpha1-adrenergic signal transduction pathways in cardiac muscle is demonstrated by their regulatory effects on cell growth (hypertrophy), contractility, chronotropy and energy metabolism.
The aim of this proposal is to determine the proximal steps in the alpha1- adrenergic signal transduction pathways that modulate hypertrophy and chronotropy in cultured, neonatal cardiac myocytes. The advantages in using cultured, cardiac myocytes for these studies include the ability of these cells to be maintained in serum-free medium for several days, and to undergo microinjection or transfection, allowing direct experimental manipulation of specific steps in the signal transduction pathway. Specifically, this proposal will seek: 1) to determine the number, type and abundance of alpha1-adrenergic receptor, G protein, and phospholipase C subtypes in cardiac muscle cells; 2) to determine the contribution of the various alpha1-adrenergic receptor subtypes in mediating hypertrophic and chronotropic responses; 3) to determine the role of specific G protein(s) in coupling the distinct alpha1-adrenergic receptor subtypes to the hypertrophic and chronotropic responses; 4) to determine if Ins 1,4,5-P3 and diacylglycerol are differential signals for hypertrophy and chronotropy; and 5) to determine the molecular basis for changes in alpha1-adrenergic responsiveness during cardiac development. The experimental approach will be to first identify potential proteins involved in the alpha1-adrenergic signaling transduction pathway, and then to perturb the pathway, by microinjecting or transfecting genes encoding these proteins or the proteins themselves, and determining the effect of this perturbation on alpha1-adrenergic-mediated hypertrophic and chronotropic responses. Hypertrophic growth will be assessed by monitoring the induction of specific marker genes or proteins for atrial naturietic factor and myosin light chain-2. Chronotropy will be determined by monitoring the beat-to-beat Ca2+ transients with the fluorescent indicator dye fura 2. The information expected from the proposed studies will begin to elucidate the molecular basis underlying the diversity of alpha1- adrenergic receptor-mediated effects in cardiac muscle during development.
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