1993 — 1997 |
Mccabe, Philip |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Cns Mediation of Conditioned Bradycardia
Why are events with emotional significance remembered with particular intensity? Current evidence suggests that the autonomic activity that accompanies emotional experiences in a way that facilitates later recall. A popular paradigm for investigating this phenomenon is the conditioned heart rate deceleration that occurs to a stimulus that has become frightening because of previous association with pain or suffering. With this NSF award, Dr. McCabe will investigate the changes that occur in neuronal firing as stimuli change meaning from neutral to frightening and then as they lose their significance through desensitization. He will use sophisticated neurophysiological techniques to record from single neurons in two brain areas simultaneously. The information he gains from studying changes in the firing patterns in these two areas will identify the steps involved in the neuronal coding of emotional meaning. This kind of information is crucial for the development of therapies designed to reverse the effects of early emotional trauma and also to control the abnormal autonomic reactivity that occurs in many cardiovascular diseases. It will also prove important for the design of neural nets for information processing, storage and retrieval.***//
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0.915 |
2001 — 2005 |
Mccabe, Philip M |
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. |
Environment, Cns, and Atherosclerosis in An Animal Model @ University of Miami Coral Gables
DESCRIPTION (provided by applicant): We have demonstrated that social behavioral factors can influence the progression of atherosclerosis in an animal model genetically predisposed to the development of disease, the Watanabe Heritable Hyperlipidemic Rabbit (WHHL). It was found that stable social conditions, accompanied by increased affiliative social behavior, slowed the progression of atherosclerotic lesions in these animals. In contrast, animals in unstable social conditions, displaying increased agonistic behavior, and animals housed singly exhibited significant aortic pathology. These data could not be explained entirely by resting plasma glucocorticoids, gonadal steroids, lipid levels, nor resting cardiovascular measures. It is hypothesized that chronic activation of the sympathetic nervous system (SNS) accelerates the progression of atherosclerosis. In addition, we will examine Central Nervous System (CNS) mechanisms underlying the regulation of the SNS and hypothalamic pituitary adrenocortical axis (HPA), focusing primarily on the roles of central corticotropin-releasing hormone (CRH) and oxytocin (OT) in the control of SNS and HPA responses. It is hypothesized that CRH, released centrally during stressful behavior, stimulates the SNS and HPA, thereby accelerating the progression of disease. In contrast, central OT, which has been linked to increased affiliative behavior, may buffer the organism during stable social conditions from the effects of stress by inhibiting the HPA axis and SNS activity. Animals housed singly exhibited low glucocorticoid levels and showed little stressful behavior, yet still developed significant atherosclerosis. These sedentary animals gained more body weight than the other groups and developed profound hyperinsulinemia, suggesting that risk factors related to the Insulin Metabolic Syndrome may be particularly important for the progression of disease in this group. The proposed work will: 1) assess the role of the SNS in behaviorally-related atherosclerosis via selective adrenergic receptor antagonists, 2) determine the role of central CRH in the regulation of SNS activity and atherosclerosis during chronic social stress via a centrally administered CRH antagonist, 3) measure changes in the release of OT in the hypothalamic paraventricular nucleus as a function of social environment through the use of chronic microdialysis, 4) determine the role of central OT in the regulation of HPA and SNS activity, and its relationship to atherosclerosis via a centrally administered OT antagonist, 5) assess the impact of dietary restriction or daily exercise on risk factors related to the insulin metabolic syndrome and atherosclerosis and in individually-caged WHHLs, and 6) examine the influence of social environment on atherosclerosis in the heterozygous WHHL, an alternative model that more closely parallels lipid status and disease progression in a large percentage of humans.
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1 |
2007 — 2011 |
Mccabe, Philip M |
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. |
Social Environment, Hyperlipidemia, Inflammation &Atherosclerosis in Whhl Rabbit @ University of Miami Coral Gables
C reactive protein; behavioral /social science research tag; pathologic process; vascular smooth muscle
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1 |
2013 — 2016 |
Mccabe, Philip M |
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. |
Social Environment, Sympathetic Nervous System & Atherosclerosis in Whhl Rabbits @ University of Miami Coral Gables
DESCRIPTION (provided by applicant): The proposed research will examine the role of social/emotional factors in atherosclerosis, and attempt to establish mechanistic links among biobehavioral risk factors, molecular mediators and clinical disease progression. This will be accomplished through the use of the Watanabe Heritable Hyperlipidemic Rabbit (WHHL), a genetic animal model characterized by hyperlipidemia and severe atherosclerosis. We have demonstrated that social environment profoundly affects the course of disease in WHHLs, such that animals in stable relationships with littermates, as opposed to WHHLs in unstable social conditions or social isolation, showed a significant decrease in the progression of atherosclerosis. An unstable social environment, characterized by agonistic behavior and emotional stress, was associated with the development of severe, advanced atherosclerotic lesions. These findings suggest that biobehavioral factors are important in the progression of atherosclerosis, even in models of disease that have strong genetic determinants. It is well established that hyperlipidemia, inflammation and oxidative stress are the proximal vascular mechanisms in atherosclerosis, but the mediators linking social/emotional behavior to these drivers of disease are not clear. One of the most likely mediators linking social environment to disease is the sympathetic nervous system (SNS), and in preliminary work, we have observed that there is SNS hyperinnervation in atherosclerotic vascular tissue. This chronic SNS structural plasticity is proposed to exacerbate vascular inflammation, oxidative stress, and the progression of atherosclerosis. The proposed work will examine whether this SNS remodeling occurs in response to social environment or to the presence of local disease. We will also assess whether preventing this SNS hyperinnervation attenuates vascular inflammation and the progression of atherosclerosis. Therefore, the specific aims of the project are: 1a.) to examine SNS innervation density of vascular tissue in WHHLs vs normolipidemic control rabbits (New Zealand White; NZW) over time as a function of social environment, and to relate these differences to the progression of atherosclerosis, 1b.) to examine SNS innervation density of other peripheral tissue in WHHLs vs NZWs as a function of social environment, and 2.) to quantify vascular SNS innervation density, inflammation and atherosclerosis in WHHLs following pharmacological antagonism of NGF's target receptor, TrkA. The proposed research represents a novel approach to understanding how known risk factors (e.g., hyperlipidemia) may interact with behavioral variables to lead to the exacerbation or attenuation of disease. This type of SNS neuronal plasticity, and the resulting enhanced vascular inflammation/oxidative stress, may represent intervention targets for behavioral and/or pharmacological therapy in cardiovascular disease.
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1 |