Wayne A. Cass - US grants
Affiliations: | University of Kentucky, Lexington, KY |
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High-probability grants
According to our matching algorithm, Wayne A. Cass is the likely recipient of the following grants.| Years | Recipients | Code | Title / Keywords | Matching score |
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| 1997 — 2001 | Cass, Wayne A | R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Recovery From Methamphetamine Induced Neurodegeneration @ University of Kentucky DESCRIPTION: (Applicant's Abstract) Methamphetamine (METH) is a potent psychomotor stimulant that has high potential for abuse in humans. METH is also a neurotoxin, affecting primarily brain dopamine (DA) and serotonin systems. The abuse potential of METH, together with its neurotoxic effects, make METH an important drug from the standpoint that chronic use by humans may lead to long-term changes in brain neurochemistry. The experiments in this proposal will focus on in vivo changes in presynaptic DA function in the striatum and nucleus accumbens (NAc) of rats treated with neurotoxic doses of METH. The experiments will test the hypotheses that METH will produce long-lasting, functional changes in DA overflow and uptake, that the magnitude and duration of these changes will be dependent on the age of the animals, and that these changes can be prevented or reversed by the recently discovered dopaminergic neurotrophic factor glial cell line derived neurotrophic factor (GDNF). The initial set of experiments will determine the short-term (1 week) effects of METH treatment on DA overflow and uptake in rats. In vivo electrochemistry will be used to map potassium-evoked (calcium dependent) overflow of DA and DA clearance (uptake) in the striatum and NAc of control and METH treated animals. In vivo microdialysis will be carried out to determine basal levels, and potassium-and d-amphetamine-evoked (calcium independent) overflow of DA and DA metabolites to confirm and extend the electrochemical studies. The second set of experiments will use the same techniques to examine the time course (1 week to 1 year) for recovery of DA overflow and uptake in rats following neurotoxic doses of METH. The third set of experiments will examine how the age of the rat during METH treatment affects the magnitude and duration of changes in DA overflow and uptake. The severity of effects and time course for recovery will be followed in young adult (3-4 months old) and middle-aged (12 months old) animals. In the fourth set of experiments GDNF, a potent dopaminergic neurotrophic agent, will be administered directly into the brain of young adult and middle-aged rats at various time points prior to, and after, neurotoxic doses of METH. The ability of GDNF to reduce or prevent METH-induced changes in presynaptic DA function, and the ability to accelerate recovery, will be monitored with in vivo electrochemistry and microdialysis. Tissue DA levels will be determined at the conclusion of all experiments as a measure of the extent of the neurotoxic lesions. It is hoped that the infor-mation derived from these experiments will increase our understanding of possible long-term consequences associated with METH abuse. |
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| 1998 | Cass, Wayne A | R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Aging and Vulnerability to 6hydroxydopamine @ University of Kentucky This application is from a new investigator and is aimed at research topic 16 - sensory and motor processing. The nigrostriatal dopamine (DA) system of the brain has been shown to play a major role in the control of movement. A gradual loss of nigrostriatal dopamine neurons occurs during normal aging in humans, and many elderly persons display one or more of the signs of Parkinson's disease without having the disease. This may indicate that older people that have parkinsonian signs may have a greater than normal loss of nigrostriatal DA. Although the cause for the normally occurring loss of midbrain DA cells in the elderly is not known, animal studies have indicated that the DA neurons of older animals may be more vulnerable to the effects of various neurotoxins. The purpose of the experiments in the present application is too determine if the nigrostriatal DA system of older animals is more sensitive to the neurotoxic effects of the dopaminergic toxin 6- hydroxydopamine (6-OHDA), and to begin to develop a model of the aging brain that is partially depleted of DA. It is hypothesized that the nigrostriatal DA system in older rats will be more sensitive to the neurotoxic effects of 6-OHDA than the nigrostriatal DA system of younger rats. The initial set of experiments will be to generate a dose- response curve in young adult animals for the DA-depleting effects of 6-OHDA. Male Fischer-344 rats (4 months old) will be given a single, unilateral injection of 6-OHDA into the right lateral ventricle. The doses examined will be 0, 50, 100, 150, and 200 mug of 6-OHDA per injection. Three weeks later, DA and metabolite levels will be measured in the striatum, nucleus accumbens, substantia nigra, and medial prefrontal cortex. Based on the results of these experiments, a dose of 6-OHDA that reduces striatal DA levels by approximately 50 percent in young adult rats will given to rats of three ages; 4 months, 18 months, and 24 months old. Three weeks later the rats will be anesthetized and in vivo electrochemistry experiments will be carried out on both sides of the brain to map out potassium-evoked overflow of DA, and subsequent clearance of DA, in the striatum. Following the experiments, post-mortem levels of DA and metabolites will be measured to determine the extent of whole tissue depletion by the 6-OHDA. The results of these experiments will help determine if the nigrostriatal DA system of the aging rat brain is more susceptible to the neurotoxic effects of 6-OHDA, and will begin to determine possible differences in presynaptic dopaminergic functioning in the aging versus younger brain in response to a neurotoxic insult. |
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| 2001 — 2005 | Cass, Wayne A | 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. |
Aging and 6 Hydroxydopamine Neurotoxicity @ University of Kentucky DESCRIPTION: (Verbatim from the Applicant's Abstract) The nigrostriatal dopamine (DA) system of the brain plays a major role in the control of movement. A gradual loss of nigrostriatal DA neurons occurs during normal aging in humans, and many elderly persons display one or more of the signs of Parkingson's disease without having the disease. This may indicate that these people have a greater than normal loss of nigrostriatal DA. An animal model of aging with a partial loss of DA neurons (ICV injection of 6-hydroxydopamine, 6-OHDA) is currently being developed by the applicant. The experiments in the present proposal will use this model to determine the extent of spontaneous recovery of presynaptic dopaminergic functioning in young, middle-aged and aged rats. In addition, the effects of the potent dopaminergic factor glial cell line-derived neurotrophic factor (GDNF) will also be examined in this model. It is hypothesized that the nigrostriatal DA system in aged rats will have a reduced capacity to recover from the neurotoxic effects of 6-OHDA compared to young rats. It is further hypothesized that GDNF will be less effective in aged animals compared to young animals both in its ability to protect against 6-OHDA and to promote recovery after the lesion. The first specific aim will examine spontaneous recovery in young (4 months old) middle-aged (14 months old), and aged (24 months old) male and female Fischer-344 rats following partial bilateral lesions with 6-OHDA. Locomotor activity, basal levels and evoked overflow of DA and its metabolites in the striata (as measured with microdialysis), and tyrosine hydroxylase immunohistochemistry studies will be carried out at several time points after the lesion to determine extent of recovery. Post-mortem measurements of tissue monoamines will be analyzed as well. The second specific aim will evaluate the ability of GDNF to prevent or reduce 6-OHDA-induced changes in locomotor activity and presynaptic dopaminergic function in the three age groups, while the third specific aim will examine the ability of GDNF to promote behavioral and neurochemical recovery from the lesion in the three age groups. The results of these experiments will help determine if the nigrostriatal DA system of the aging brain has the same capacity to recover from a neurotoxic insult as that of younger animals, and will begin to evaluate age-related differences in response of nigrostriatal DA neurons to neurotrophic factors. |
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| 2007 — 2008 | Cass, Wayne A | 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.) |
Calcitriol and Methamphetamine Neurotoxicity @ University of Kentucky [unreadable] DESCRIPTION (provided by applicant): Methamphetamine (METH) is a potent psychomotor stimulant that has high potential for abuse in humans. METH is also a neurotoxin, affecting primarily central dopamine (DA) and serotonin (5-HT) neurons. The abuse potential of METH, together with its neurotoxic effects, make METH an important drug from the standpoint that chronic use by humans may lead to long-term or permanent changes in brain neurochemistry and function. The experiments in this R21 exploratory grant proposal will focus on the ability of calcitriol, the active metabolite of vitamin D, to prevent the neurotoxic effects of METH on brain monoamine neurons and to restore function to damaged neurons. Several reports have indicated that calcitriol provides signification neuroprotection against various lesions, possibly by upregulating trophic factors such as GDNF. GDNF has been shown to have protective and restorative effects for brain DA neurons. Thus, it is possible that systemic administration of calcitriol may be able to prevent or reduce METH-induced damage to monoamine neurons and help restore function to neurons previously damaged by METH. It is hypothesized that calcitriol will protect against the neurotoxic effects of METH on striatal DA and 5-HT terminals, and the calcitriol will be effective in reversing METH-induced damage to striatal DA and 5-HT terminals. This hypothesis will be tested by addressing the following two specific aims: 1) Does pretreatment with calcitriol prevent or reduce METH-induced reductions in striatal monoamine release and content? And 2) Can calcitriol treatment accelerate recovery of striatal monoamine release and content in animals previously administered neurotoxic doses of METH? For these experiments rats will be treated with calcitriol before or after administration of saline or neurotoxic doses of METH. Microdialysis studies and post-mortem monoamine analyses will be carried out to investigate protective and restorative effects. Calcitriol induced upregulation of GDNF will be examined as an initial investigation into the mechanism of any neuroprotective or restorative effects observed. [unreadable] [unreadable] Relevance to Public Health: METH abuse and addiction is a major public health issue in the United States. The results of the experiments in the proposal will help determine the extent to which calcitriol can protect against the neurotoxic effects of METH, and if calcitriol can restore damage resulting from neurotoxic doses of METH. IF calcitriol proves effective, the results of the proposal studies could lead to novel therapeutic strategies for treating individuals who chronically abuse METH. Furthermore, if calcitriol is effective, it could have therapeutic applications in other disease processes where there is a loss of monoamine neurons, such as in Parkinson's disease. [unreadable] [unreadable] [unreadable] |
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| 2007 — 2008 | Cass, Wayne A | 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.) |
Calcitriol-Induced Restoration of Dopamine in a Model of Parkinson's Disease @ University of Kentucky [unreadable] DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder that affects over one million people in the United States. Current therapies for PD offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or even restore function to damaged neurons would be of substantial benefit. Trophic factors, such as glial cell line-derived neurotrophic factor (GDNF), are promising therapeutic candidates because of their neuroprotective and neurorestorative effects on nigrostriatal dopamine (DA) neurons in animal models of PD. However, while the protective and restorative effects of GDNF have been well documented, the use of exogenous GDNF is problematic as it does not cross the blood brain barrier and must be administered directly into the brain. Thus, non-invasive treatments that can upregulate endogenous levels of trophic factors such as GDNF could be of significant benefit to individuals suffering from PD. Calcitriol, the active metabolite of vitamin D, has been shown to upregulate GDNF levels in the brain, including in the striatum and substantia nigra, and is partially protective against various CNS insults. The systemic administration of calcitriol may therefore be able to help restore normal function to DA neurons damaged by degenerative processes in patients with PD and may be able to slow down or halt progression of the disease. The proposed experiments will examine the effects of calcitriol in a 6-hydroxydopamine (6-OHDA) animal model of early PD. It is hypothesized that calcitriol will be effective in reversing 6-OHDA-induced behavioral changes and damage to nigrostriatal DA neurons in rats. The proposed experiments will determine the extent to which calcitriol treatment promotes recovery of behavior and striatal DA release and content in animals previously administered neurotoxic doses of 6-OHDA. Four weeks after administration of 6-OHDA rats will begin treatment with various doses and time courses of calcitriol. Behavior, in vivo microdialysis, and post- mortem analyses will be used to evaluate the restorative effects of calcitriol. As PD usually affects older individuals, young, middle-aged and aged rats will be examined to provide a more comprehensive evaluation of the effects of calcitriol in this model. These studies will begin to define the restorative effects of calcitriol on behavior and on functional measures of DA terminal integrity, and determine if the effects of calcitriol are dependent on the age of the animal. to Public Health: The proposed studies will determine if calcitriol can help restore normal behavior and normal levels of dopamine release and content in an animal model of Parkinson's disease. If calcitriol proves effective, the results of the experiments in this proposal may lead to novel and improved treatment strategies for persons suffering from this debilitating disease. In addition, as calcitriol is already approved for clinical use in humans for other diseases, evidence of efficacy in animal models of Parkinson's disease would facilitate initiation of clinical trials. [unreadable] [unreadable] [unreadable] |
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