1987 — 1990 |
Adams, Michael E |
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. |
Novel Synaptic Antagonists @ University of California Riverside
The proposed research is principally aimed at the discovery and development of novel synaptic receptor toxins as probes to augment the understanding of synaptic transmitter mechanisms in the nervous system. The focus is on synaptic transmission mediated by amino acids and peptides. Spiders have evolved highly potent venom toxins to immobilize their insect prey. Paralysis results from a "curare-like" blockade of skeletal neuromuscular transmission which, for insects, involves amino acid transmitters. The applicant seeks to investigate the physiological basis for synaptic block caused by novel toxins recently isolated form Orb Weaver and Funnel Web spider venoms. The toxins appear to function as specific receptor antagonists affecting L-glutamate and L-aspartate transmission at nerve-muscle junctions. They are low molecular weight substances which exhibit novel structural features suggestive of a pseudo-peptidic character. Estimated potencies of the toxins are in the micromolar to nanomolar range, making them among the most active amino acid antagonists thus far described. Electrophysiological techniques are to be used for the analysis of toxins activity on model synaptic preparations mediated by glutamate, aspartate and the pentapeptide, proctolin. The applicant further proposes to conduct a systematic study of spider venoms designed to uncover new toxins affecting amino acid and peptide synaptic transmission. This will be accomplished by combining methods for HPLC purification and bioassay of toxins on in vivo and in vitro synaptic preparations. Excitatory amino acids are considered a major class of brain neurotransmitters. Amino acid receptor antagonists have already shown promise as a potential class of new central anticonvulsants which could ultimately lead to improved therapeutic approaches to seizure syndromes in the brain. The spider toxins may be the most potent and specific amino acid receptor antagonists yet discovered. As such, they hold promise for the creation of effective pharmacological and biochemical probes useful in developing studies and therapies involving amino acid transmitter mechanisms.
|
1 |
1991 — 1994 |
Adams, Michael E |
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. |
Novel Synaptic Antagonists From Venoms @ University of California Riverside
The proposed research is aimed at the discovery and exploitation of synaptic neurotoxins from spider venoms for studies of chemical signaling and excitability in the nervous system. Recent progress demonstrates the occurrence in spider venoms of neurotoxins possessing remarkable potency and specificity for three ion channel types operating at the neuromuscular junction: i) acylpolyamine toxins acting as postsynaptic antagonists of ligand-gated receptor channels (alpha-agatoxins), ii) peptide toxins acting presynaptic activators of voltage-sensitive sodium channels (mu-agatoxins) and peptide toxins acting as presynaptic antagonists of voltage-sensitive calcium channels (omega-agatoxins). The high affinity and specificity of these neurotoxins make them potentially useful in the characterization, localization and isolation of ion channel proteins. The principle objective of the project is to use the omega-agatoxins and other voltage-sensitive calcium channel (VSCC) antagonists to establish functional roles for biophysically and pharmacologically distinct calcium channel subtypes. The omega-agatoxins will be characterized with respect to their primary structure and differing specificities for VSCC subtypes in various tissues across phylogenetic groups. This will be determined by isolation, continued structure determination and testing on nerve and muscle preparations from insects, amphibians, birds and mammals. Next, the different VSCC specificities of the omega-agatoxins will be exploited in pharmacological investigations designed to probe transmitter release mechanisms at the neuromuscular junction and in the central nervous system. These experiments are designed to reveal possible subcomponents of the transmitter release process and determine if these are related to subtypes of VSCC. Results from these experiments will be correlated with VSCC analyses in model cellular preparations amenable to direct measurement of Ca currents under voltage clamp conditions. The second major aim of the study is to continue with a systematic search for novel ion channel antagonists in spider venoms. Several nerve and muscle preparations in use or available through collaborations with colleagues will be used to assay candidate toxins for influences on mechanisms of transmitter release at the neuromuscular junction, calcium current in neuronal cell bodies, and 45Ca flux and neurotransmitter release in synaptosomal preparations. Calcium channels are crucial to a wide array of cellular processes, including secretion, proliferation, signaling, metabolism, plasticity, and neural organization. The proposed studies aim to increase basic knowledge regarding the roles played by these important membrane proteins, and may lead to accelerated development of therapeutic treatments for neural degenerative syndromes connected with ion channel function.
|
1 |
1995 — 2000 |
Adams, Michael [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Modulation of Calcium Channels in Neurons @ University of California-Riverside
9511020 Adams Nerve cells communicate with each other by means of chemical signals called neurotransmitters and neurohormones. The arrival of electrical impulses at nerve endings release tiny amounts of neurotransmitters acting locally or much larger amounts of neurohormones acting at longer distances; both stimulate the electrical activity in neighboring nerve cells. The release of these chemical signals depends on the brief entry of calcium to nerve terminals, a process that is highly regulated by "calcium channels". Small amounts of calcium enter for neurotransmitter release, whereas larger and longer periods of calcium entry are necessary for the release of hormones. These differences are to a large extent dictated by variations in the properties of different calcium channels. Dr. Adams and his colleagues are working to define the properties of calcium channels in different types of nerve cells, ranging from motoneurons to neuroendocrine cells, using a combination of electrophysiology and pharmacology. The kinetics of calcium channel opening and closing as well as their sensitivities to different drugs and toxins will be used to classify them into different groups and to associated them with different functions in nerve cells. Potential applications of these studies are the development of pharmaceuticals and pest control agents.
|
0.915 |
1996 — 2001 |
Adams, Michael [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Chemistry and Biology of Ecdysis-Triggering Hormones @ University of California-Riverside
Adams 9514678 Insect growth and development is associated with repeated shedding of the old exoskeleton or cuticle in a process called ecdysis. The successful performance of this complex behavior is crucial to the survival of developing insects. It appears that a newly described novel endocrine system regulates ecdysis in moths and may be important to this develomental process in all insects. This novel endocrine system appears to produce multiple hormones. The identification of these hormones is paramount to Dr. Adams' research endeavor. Once these factors have been chemical identified, reagents will be prepared that allow the localization and quantification of the hormones in the insect during development. Finally, the site and mechanism of ecdysis-triggering hormone action will be elucidated. This unique endocrine system provides opportunities to study the hormonal regulation of development and behavior from the molecular to the organismal level including information regarding the regulation of hormone sythesis, release and physiological action. Furthermore, premature administration of ecdysis-triggering hormone to early stages of larvae and pupae is lethal, these hormones may prove to be of great commercial significance in the biological control of insect pests.
|
0.915 |
1997 — 2002 |
Adams, Michael E |
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. R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Molecular Physiology of the Epitracheal Endocrine System @ University of California Riverside
DESCRIPTION: (provided by the applicant): Insect development and behavior are orchestrated by hormone-driven signaling cascades. We have identified ecdysis-triggering hormones (ETHs) in flies (Drosophila, Musca) and moths (Manduca, Bombyx), demonstrated their functional roles in regulating in the ecdysis sequence, and established that ETH is obligatory for insect survival. The overall objective of this proposal is to provide a better understanding how gene expression and hormones regulate developmental and behavioral processes. Long-range goals are to provide basic knowledge eventually applicable to management of human disease vectors, e.g., mosquitoes. The specific objectives of this proposal are to define the ETH system in human disease vectors, elucidate regulatory roles of steroids in ETH signaling, and to understand the physiological roles of ETH in orchestration of the ecdysis sequence. The first objective (Specific Aim I) will be to establish the presence of the ecdysis-triggering hormone (ETH) in mosquitoes, provide basic knowledge of the ecdysis sequence in these animals, and determine the consequences of disrupting ETH signaling. For the second and third specific aims, we will make use of model systems to examine hormonal mechanisms regulating ETH synthesis and secretion in the lnka cell (Specific Aim II) and to define cellular and molecular targets for ETH (Specific Aim Ill). The ecdysis sequence is an excellent model for relating steroid and peptide signaling processes to physiology and behavior. The fruit fly Drosophila melanogaster provides powerful genetic tools for deletion and conditional expression of key genes involved in these processes, while the moth Manduca sexta offers advantages for endocrinological and physiological manipulations. Use of these models will allow us to pose testable hypotheses at many levels, and to mobilize genetic and cellular approaches appropriate to each objective. The simplicity of the epitracheal endocrine system, composed of glands containing only 1-3 cells, provides an excellent model for examination of endocrine function at the cellular, developmental, and molecular levels. Since -ecdysis is crucial for successful development of insects and other arthropods, understanding the regulatory mechanisms which underlie these precisely timed and synchronized processes should allow in the future for more sophisticated approaches to the management of insect borne disease.
|
1 |
2003 — 2012 |
Adams, Michael E |
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. |
Molecular Physiology of the Epitrachael Endocrine System @ University of California Riverside
[unreadable] DESCRIPTION (provided by the applicant): Insect development and behavior are orchestrated by hormonal signaling cascades. We have identified a novel system of epitracheal glands, and associated peptidergic Inka cell, which secretes ecdysis-triggering hormones (ETHs). We will investigate the molecular physiology of this regulatory endocrine system in a genetic model (fruit fly, Drosophila) and a physiological model (moth, Manduca sexta). We previously demonstrated functions for ETHs in regulation of respiratory dynamics and a behavioral sequence associated with ecdysis, and established that ETH is an obligatory chemical signal for survival. The overall objective of this proposal is to provide a better understanding of how gene expression and hormones regulate developmental and behavioral processes. Long-range goals are to provide basic knowledge of chemical signaling processes in organisms applicable to development of therapeutics and management of insect vectors of human diseases. The first objective of the proposal is to define developmental, stage-specific functions for ETHs and to identify neuropeptides controlling their secretion. We will construct conditional promoters of ETH expression to rescue null mutant flies through each stage of development, in order to evaluate the physiological consequences of ETH deficits in later stages of ontogeny. Additional chemical signaling mechanisms, including the neuropeptide corazonin, will be evaluated for their regulation of ecdysis. For the second specific aim, we will examine the steroid regulation of cell-specific expression of ETHs and their release from Inka cells. Finally, our third specific aim will be to identify the nervous system receptor(s) for ETHs and the downstream neuronal targets of ETH action in the CNS. The ecdysis sequence is an excellent model for relating steroid and peptide signaling processes to physiology and behavior. Drosophila offers powerful genetic tools for deletion and conditional expression of key genes involved in these processes, while the moth Manduca offers advantages for endocrinological and physiological manipulations. Use of these models will allow us to pose testable hypotheses at many levels, and to mobilize genetic and cellular approaches appropriate to each objective. The simplicity of the epitracheal endocrine system, composed of glands containing only 1-4 cells, provides an excellent model for examination of endocrine function at the cellular, developmental and molecular levels. Since ecdysis is crucial for successful development of insects and other arthropods, understanding the regulatory mechanisms which underlie these precisely timed and synchronized processes should allow in the future for more sophisticated approaches to the study of basic physiology and behavior. [unreadable] [unreadable]
|
1 |