Richard C. McCarty, PhD - US grants

In this proposal, I have outlined a program of research which focuses on homeostatic regulation of the sympathetic nervous system of laboratory rats during chronic exposure to stressful stimulation. The stress concept was first introduced by Hans Selye nearly 50 years ago. In spite of extensive research on the stress responses of animals and humans over the years, there remains a glaring absence of a soundly developed and widely accepted theoretical framework for this field of research. In this proposal, several experiments are described which will clarify the underlying adaptive responses of the sympathetic nervous system to acute versus chronic exposure to stressful stimulation. In the first experiment, adult male laboratory rats will be stressed 30 minutes per day for 0, 1, 7, 14, or 28 consecutive days in one of the following conditions: immobilization (IM), exposure to intermittent, inescapable footshock (FS), or immersion in 18 degrees C water (CI). To control for the element of predictability, another group of rats will be exposed randomly to 1 of the 3 stressors for 7, 14, or 28 consecutive days. Plasma levels of norepinephrine and epinephrine will be measured in blood samples taken before, during, and after stressful stimulation as an index of sympathetic-adrenal medullary activity. In addition, the effects of these stress regimens on catecholamine biosynthetic enzyme activities and catecholamine content of several sympathetically innervated tissues will be quantified. In a second series of "Cross-over" experiments, rats will be stressed chronically in one condition and then acutely in another (i.e. chronic IM-acute FS; chronic FS-acute CI; chronic CI-acute IM) to examine the sympathetic responsiveness of a chronically stressed animal to a novel stressor. The results of this research will provide an extensive empirical base for refining and extending the conceptualization of stress. In addition, it will serve as a foundation for directing the research efforts of my laboratory toward the study of central neuronal adaptations to stressful stimulation in laboratory animals. These findings will be of direct relevance to several stress-related disorders in humans, including peptic ulcer disease, hypertension, depression and coronary artery disease.

The experiments described in this proposal will evaluate the role of the early maternal environment in the development of sympathetic nervous system hyperreactivity and elevated blood pressure in the spontaneously hypertensive (SHR) rat, an animal model of human essential hypertension. Our experimental approach will involve altering the early maternal environment of SHR and Wistar-Kyoto (WKY) normotensive litters by reciprocal cross-fostering and examining the effects of this treatment on the development of sympathetic-adrenal medullary activity and behavior of rats while undisturbed and during acute exposure to stressful stimulation. Specifically, SHR and WKY litters will be reared under 1 of 3 conditions: (a) control- rearing of the litter by the natural mother; (b) in-fostered- rearing of the litter by a foster mother of the same strain; or (c) cross-fostered- rearing of the litter by a foster mother of the opposite strain. With additional control groups of SHR and WKY litters, we will determine if the effects of the maternal environment on sympathetic activity and hypertension are mediated by strain differences in maternal behavior or by a hypertensinogen transmitted through the milk. To assess the effects of the maternal environment on the development of the sympathetic-adrenal medullary system, rats of the 6 strain-treatment groups (ages 2,4,8,12,16, or 20 days) will be injected with saline or insulin and sarcrificed 3 hours later. The induction of ornithine decarboxylase in heart and the depletion of epinephrine from the adrenal medulla will serve as markers of tissue responses to insulin-induced sympathetic stimulation. In addition, we will test SHR and WKY male rats at 6, 12 or 18 weeks of age to determine possible long term effects of the maternal environment on behavioral and physiological responses. For rats at each age, we will measure open field behavior and basal values of heart rate, mean blood pressure and plasma levels of nerepinephrine and epinephrine and changes in each of the above parameters following acute exposure to intermittent footshock. The results of this research will provide important information regarding the impact of the preweaning maternal environment on the development of the sympathetic-adrenal medullary system in genetically hypertensive and normotensive rats. Further, our studies will clarify in post-weaned SHR rats the significance of sympathetic hyperresponsiveness during acute stress as a risk factor for the development of hypertension.

We propose an innovative pathway to the PhD for substantially broadening the participation of underrep-resented minorities in materials science, linking multiple NSF-funded materials research programs (CREST and REU) at the partnering institutions. The nucleus of this I3 will be the Fisk-Vanderbilt Masters-to-PhD Bridge program, with its strong track record of enabling students to earn a Master?s degree at Fisk as a stepping stone to the PhD program at Vanderbilt. Vanderbilt and Fisk are joined in this I3 by Dela-ware State University (DSU). Our program?s path to the PhD emphasizes research engagement and de-liberate mentorship by faculty at PhD-granting institutions to help students cross the aspirational and insti-tutional transitions.
We will directly address all of the I3 program goals. In so doing, with the I3 funding requested here we will enable at least 2 underrepresented minority graduate students toward the PhD in Materials Sci-ence each year, representing ~20 times the national institutional average. Over the 5 years of requested I3 support, this represents 10 individuals supported by I3 funding who will complete, or be on the path to-ward completing, the PhD. By itself this is a substantial, tangible result of our innovation and integration and a vital contribution to the STEM workforce.
Arguably even more important for the long-term sustained impact and institutionalization of this program, and the eventual expansion of our Masters-to-PhD Bridge model into additional STEM disci-plines, will be the foundation laid here for truly understanding how best to design the architecture of our model to ensure successful portability into new disciplinary and institutional contexts.
We will:
1.
Expand the Fisk-Vanderbilt Masters-to-PhD Bridge Program to include Materials Science. Key faculty have been identified as the ?bridge builders? following the model of the existing program in physics. Leveraging significant institutional support already in place, we will ex-pand and deepen the footprints of our NSF-funded CREST projects and enhance their sus-tainability.
2.
Extend the Bridge Program in partnership with Delaware State University. The resulting Fisk-Vanderbilt-DSU Masters-to-PhD Bridge Program will permit students to transition from the MS at Fisk to the PhD at Vanderbilt, from the MS at Fisk to the PhD at DSU, or from the MS at DSU to the PhD at Vanderbilt. The result will be increased synergy and collaboration across our NSF-funded CREST and REU programs, reducing the artificial boundaries that can so often impede student mobility across educational junctures.

Broadening Participation in Materials Science through Institutional Integration of a Masters-to-PhD Bridge Program at Fisk, Delaware State, and Vanderbilt Universities brings together NSF/EHR awards from the IGERT and CREST programs, as well as other work, around the I3 integrative themes for broadening participation, critical educational junctures, and the integration of research and education.