1987 — 1989 |
Millard, William J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gonadal Steroid Modulation of Brain-Pituitary Function
The modulatory role of gonadal steroids in regulating sex- dependent growth hormone (GH) secretion will be studied during development through reproductive senescence. A series of interrelated experimental approaches will be used to clarify the level of gonadal steroid control of GH secretion (hypothalamic, pituitary and peripheral organs). In the course of these studies, GH secretory patterns throughout life in the rat will be defined. We anticipate that the results of these studies will advance our understanding of the development and maintenance of GH secretory dynamics and help explain sex-related differences in growth rates. The first series of experiments will define both a dose-response and time course for gonadal steroid action on GH secretory patterns using a chronically-cannulated rate in vivo model. Direct pituitary effects of steroids will be assessed by observing the GH response to GH-relating factor (GRF). A second series of experiments will investigate the hypothesis that gonadal steroids modulate GH secretion via a novel mechanism termed a "steroid sensitive switch". The existence of the "steroid sensitive switch" in adult rats will be studied by utilizing a paradigm involving the exposure of male and female rats to alternating courses of steroids. In addition, the development of the "steroid sensitive switch" will be studied beginning with gestational life through adulthood. A third series of experiments will focus on GH secretory patterns throughout the life of male and female rats. Studies will investigate GH secretory patterns during puberty, during the estrous cycle in adult female rats and during various stages of reproductive senescence in both male and female rats. Studies will extend to investigating GRF-induced GH secretion during these various stages of life. Finally, the metabolic clearance rate and half-life components of GH in male and female rats will be determined to establish whether gonadal steroids play a role in modulating these parameters.
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1994 — 2002 |
Millard, William J |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core-- Neurochemistry
The major goal of this program project to develop drugs that may prove beneficial to Alzheimer's disease (AD) patients. However, paramount to the establishment of a drug or class of drugs that may have therapeutic applications in AD is the establishment of alterations (improvements or possibly further deterioration)in the neurochemical profile while undergoing drug therapy. It is therefore, the primary focus of this Neurochemical Core to establish a central laboratory facility which will support the various projects outlined in the program by providing assay service for a number of monoaminergic, amino acid and peptidergic neurochemical markers. The services provided will be as follows: To provide radioimmunoassay (RIA) and enzyme-linked immunoabsorbant assay (ELISA) service for various neuroactive peptides (corticotropin releasing hormone [CRH], neuropeptide Y [NPY], and somatostatin) and neuroactive peptides (mouse/rat beta-nerve growth factor [beta-NGF]) as well as anterior pituitary hormones (thyroid stimulating hormone [TSH]). To provide high performance liquid chromatography (HPLC) analysis of various monoaminergic neurotransmitters (norepinephrine, dopamine, epinephrine, serotonin) and their respective metabolites (homovanillic acid [HVA], 3,4-dihydroxyphenylacetic acid [DOPAC], 5-hydroxyindoleacetic acid [5- HIAA] or precursors (tryptophan [TRP]) and amino acid neurotransmitters (e.g. glutamate, glutamine, aspartate, glycine, gamma aminobutyric acid [GABA] and taurine). To provide radiometric analysis of various markers of cholinergic function (high affinity choline uptake, acetylcholine release and choline acetyltransferase [CAT] activity) in both synaptosomal preparations and cells from neuron-enriched cell cultures. To provide radioenzymatic analysis of glutamic acid decarboxylase (GAD) activity by monitoring the release of 14CO2 in both fresh and frozen brain tissue. To provide analysis of beta-adrenergic function following prolonged brain exposure to chemical delivery systems for analogues of catecholamines and beta-adrenergic agonists. Thus, the Neurochemistry Core will be integral to this program project by providing analytical service for the monitoring of the status of neurotransmitter systems while selected drugs undergo both preliminary and, perhaps, more detailed screening for potential therapeutic uses in the treatment of AD and related disorders.
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