1988 — 1992 |
Diz, Debra I. |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Angiotensin Ii Binding Sites and Function in the Medulla @ Cleveland Clinic Foundation
The discovery that angiotensin II (Ang II) is present in central nervous system (CNS) neurons and pathways which are believed to be involved in cardiovascular (CV), fluid, and electrolyte regulation suggests that the peptide may function as a neurotransmitter (NT) or neuromodulator, as well as a circulating hormone. However, in addition to localization within the CNS, for Ang II to be recognized as a NT the following criteria must be met: 1) Release in response to physiological stimuli; 2) Identification of receptors in suitable target neurons; and, 3) Demonstration of physiologically significant responses. The objective of this proposal is to address two of the above criteria by: 1) demonstrating the anatomical origin and pharmacological characteristics of saturable, high affinity Ang II binding sites found in the dorsomedial medulla oblongata (DMM) and the intra- and extracranial segments of the vagus nerves (No. 2 above); and, 2) relating these findings to the production of CV responses following injection of Ang II into nuclei of the DMM at physiologically relevant doses (No. 3 above). By the use of the sensitive, quantitative "in vitro" autoradiography technique, characteristics of Ang II binding in the DMM and vagus nerve of dogs will be determined in terms of density, saturability, affinity, and ligand selectivity before and following vagotomy, nodose ganglionectomy, and transection of the rostral solitary tract in the medulla. The anatomical relationship of Ang II binding to neurons and pathways in the DMM will be examined initially at the light microscopic level by correlating: 1) the distribution of Ang II binding sites with cytoarchitectural subdivisions of the canine nucleus tractus solitarii, area postrema, and dorsal motor nucleus of the vagus; and, 2) the pattern of Ang II binding sites to neurons and fibers containing substance P, or synthetic enzymes such as tyroxine hydroxylase. The relationship between changes in Ang II binding following sino-vagal deafferentation or de- efferentation of the DMM and alterations in hemodynamic responses produced by microinjection of femtomole doses either Ang II or Ang II antagonists into these areas will be evaluated in both anesthetized and unanesthetized animals. Changes in density and affinity of Ang II binding sites in the DMM and hypothalamic- hypophysial region will be examined following maneuvers known to result in chronic alterations in cerebrospinal fluid or plasma Ang II. These studies will provide essential information about the contribution of specific DMM neurons and pathways to Ang II binding sites in this region, the relationship of binding with NT- identified systems, and factors which regulate the binding sites. Finally, microinjection studies will provide insights into Ang II's role in modulation of CV function and interaction with reflex regulation of blood pressure.
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1 |
1994 — 1997 |
Diz, Debra I. |
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. |
Angiotensin Receptor Function in the Dorsal Medulla
The objectives are to extend recent findings of interactions with various transmitters (TRs) to determine whether direct or indirect actions of angiotensin peptides mediate the acute CV and baroreceptor effects. Preliminary data suggest that Ang II increases basal release of substance P (SP), but tends to reduce SP release evoked by high potassium. Moreover, others showed that Ang II causes excitation of nodose ganglion neurons, after which a partial depolarization exists. This would tend to reduce responsiveness to a subsequent stimulus. On this basis, my new hypothesis is that Ang II releases SP or norepinephrine (NE) from post- synaptic cells to mediate the acute hypotensive and bradycardic effects. However, Ang II inhibits (or does not facilitate) SP release from vagal afferent fibers when the baroreceptor reflex is activated, leading to attenuation of the baroreceptor reflex. AIM I is to complete the pharmacological profile of the Ang II binding sites in the DMM by determining the Ang receptor subtype(s) mediating release of SP, NE and prostaglandins (PGs) from DMM slices using subtype selective antagonists. These studies are based on our finding of a topographic distribution of DMM receptors with differential sensitivity to AT1 and AT2 competitors. AIM II is to determine whether dose-related CV effects of Ang peptides are linked to release of SP, NE or PGs. Localized injections of relatively specific neurotoxins and pharmacologic antagonists for the above TRs, and synaptic blockade will be used to assess whether the blockade will alter the acute CV responses to microinjections of Ang peptides in the DMM. While the acute CV effects of Ang peptides in the DMM appear to mimic activation of the reflex (hypotensive and bradycardic), Ang II infusions peripherally or centrally inhibit the baroreceptor reflex. Ang II and Ang-(1-7) differentially alter release of SP, NE and PGs, and have opposite effects on the reflex. Thus the opposite effects of Ang II versus Ang-(1-7) on the baroreceptor reflex are a consequence of differential effects on SP, NE, and PGs release. AIM III will determine whether blockade or depletion of the above TR systems alters modulation of the reflex resulting from the Ang peptides. Parallel microdialysis experiments before and during activation of the reflex will verify that release of the particular TRs is modulated by the Ang peptides in a manner consistent with the predicted effects on the reflex.
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1 |
1994 — 1998 |
Diz, Debra I. |
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. |
Brain Angiotensin Receptors--Expression and Regulation
The work outlined in this project builds upon our demonstrations that receptor density, affinity and subtype profile are altered in the brain of rats with genetic hypertension [spontaneously hypertensive rats (SHR)] or after ICV infusion of Ang peptides. We will attempt to determine the potential mechanisms for these changes in receptors by studies in Ren-2 transgenic (TG) rats, a genetic model of hypertension associated with elevated brain and adrenal Ang peptides. In both TG rats and SHR, receptor binding is lower in the dorsomedial medulla of rats treated chronically with the converting enzyme inhibitor lisinopril. The reduction in binding is not related solely to the reduction in pressure that occurs, but may be dependent upon central changes in Ang peptide levels. Thus, the pattern of distribution and density of Ang receptors, binding affinity, subtype profile an ligand selectivity [i.e., for Ang- (1-7), Ang-(2-8)], and AT1 receptor mRNA will be determined initially and after treatments that control the level of arterial pressure, change the level of specific Ang peptides, or both. Correlations will be made with peptide levels in plasma and tissues determined in Projects 1 and 6 during the development of the hypertension, and during treatment with agents that interfere with the action of the renin-angiotensin system (RAS). The second major goal is to establish whether functional relationships exist between release of specific transmitters and prostaglandins in isolated brain slices and the observed changes in receptors. These studies in isolated systems in vitro using relatively intact tissues (brain slices) will complement studies investigating signal transduction mechanisms in isolated cell system in Project 3. In addition, alterations in receptors in receptor density or profile and any parallel changes in responsiveness observed in vitro, will also complement studies of Ang peptide physiology and function in intact animals in Project 1, and 4-6.
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1 |
1997 — 2002 |
Diz, Debra I. |
T35Activity Code Description: To provide individuals with research training during off-quarters or summer periods to encourage research careers and/or research in areas of national need. |
Short-Term Research Training For Minority Students @ Wake Forest University Health Sciences |
1 |
1999 — 2002 |
Diz, Debra I. |
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. |
Regulation of Angiotensin Peptide Receptors
Ang-(1-7) activates the vasodilator systems which oppose the hypertensive At1-mediated actions of Ang II. We propose three aims to investigate the potential mechanisms for the actions of Ang-(1-7). Aim 1: A novel non-At1, non-AT2 receptor [AT(1-7)] is responsible for the hemodynamic and vascular actions of Ang-(1-7). 125I-[Sar/1-Thr/8]Ang II binding, in the presence of blocking concentrations of AT1 and AT2 receptor antagonists, demonstrated a novel Ang-(1-7) receptive site sit mesenteric artery and aorta of SHR treated with a combination of lisinopril/losartan. The binding site displayed a pharmacological profile with agonists and antagonists that previously characterized in endothelial cells. We will now determine whether this receptor is unique to the vasculature or exhibits a more widespread distribution (kidney, heart and brain) using receptor binding techniques. Aim 2: Ang-(1-7) actions blocked by At1 or AT2 receptor antagonists are not attributable to classical AT1 or AT2 receptors. In addition to the actions of Ang-(1- 7) at the novel non-AT1 non-AT2 AT(1-7) receptor, several actions of Ang-(1-7) are similar to Ang II or are blocked by AT1 or AT2 receptor antagonists. Ang-(1-7) generally displays low affinity for typical AT1 or AT2 receptors and is not associated with vasoconstrictor, pressor or drinking responses. Thus, we propose that isoforms of AT1 or AT2 receptors are responsible for the actions of Ang-(1-7) that are blocked by AT1 or AT2 receptor antagonists. We will use receptor knockout mice to show that the Ang-(1-7) actions or binding sites inhibited by AT1 or AT2 receptor antagonists do not persist in these receptor knockout animals. We will also characterize the protein forms of At1 and AT2 receptors known to exist in various tissues for differences in pharmacology toward Ang-(1-7) and [D-Ala/7]-Ang-(1-7). Aim 3: Ang-(1-7) counteracts the actions of Ang II at the AT1 receptor by desensitization and/or down-regulation of the AT1 receptor via homologous (through prostaglandins or nitric oxide) mechanisms. Acute and chronic exposure to elevated Ang-(1-7) decreases AT1 receptors and AT1 receptor-mediated responses in brain, kidney and cells in cultured. Prostaglandins causes heterologous down-regulation of other receptors and decrease in AT1 receptor mRNA with nitric oxide are reported. Alternatively, Ang-(1-7) acts as a weak agonist at the AT1 receptor, in a process similar to homologous receptor regulation. Preliminary studies in CHO-AT/1A cells indicated a direct effect of Ang-(1-7) on the AT/1A receptor, consistent with agonist-induced homologous down-regulation. We will use in vivo and in vitro models to determine the effects of acute and long-term treatments with Ang-(1-7) on AT1 receptor affinity and density and AT1 receptor mRNA by RT-PCR in the presence or absence of cyclooxygenase or nitric oxide synthase blockade.
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1 |
2001 — 2005 |
Diz, Debra I. |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Wake Forest University School of Medicine Prep Scholars @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): This program is designed to provide interim positions for post-baccalaureate students interested in pursuing graduate education. The focus is on research training under a mentor who will provide a supportive laboratory environment to develop the student's potential for a career in biomedical research. The Program Director will assign students to mentors in consultation with the selection committee and according to the students stated interest on the application. Recruitment will be by visiting area minority institutions, national mailings, a web site, and contact with students involved in other research training programs at the institution. The program takes advantage of broad, multidisciplinary research activities at Wake Forest University School of Medicine (WFUSOM) and the ongoing efforts and commitment of the Dean of the Graduate School of Arts & Sciences to increase diversity in all programs. We will provide training in a laboratory setting to meet the following goals and objectives: 1) increase the number of minority students applying to and entering the various graduate programs at WFUSOM from 6% to 12% over five years; 2) improve the GRE scores of PREP participants; 3) have 100% retention of PREP Scholars in graduate programs and 4) have 100% of the PREP participants apply, 75% attend graduate school or an M.D./Ph.D. program and 50% enter programs at WFUSOM. The program will include the opportunity to take established courses to strengthen the academic scientific background of the student, based on the particular individual's area of interest and prior strengths and weaknesses. Other courses/information will be provided to improve scores on the GRE, to introduce responsible conduct of science, to improve laboratory math skills, to improve application and resume preparation, and to inform on biomedical graduate programs at WFU in particular and graduate education in general. We will introduce students to biomedical research via hands-on participation in a research project and to critical scientific evaluation and presentation of journal articles by participation in a journal club. This will also provide experience in scientific writing and speaking as will the presentation of their research project as a slide and poster presentation each year as part of an intramural Research Day and symposium as well as part of a national scientific meetings. Students will be exposed to research faculty, both basic science and clinical, to foster a long-term commitment to pursue a career in the medical sciences through an experience that exemplifies the excitement and challenges of research. The program includes mentors from virtually all graduate departments. These educators are established scientists with research programs that are supported by extramural funds. Evaluation of the program by students and mentors will be performed annually. In addition, a questionnaire will be sent biennially for follow-up of previous participants.
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0.96 |
2003 — 2021 |
Diz, Debra I Tallant, Ann Ann |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. T35Activity Code Description: To provide individuals with research training during off-quarters or summer periods to encourage research careers and/or research in areas of national need. |
Excellence in Cardiovascular Sciences Summer Research @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): The renewal of this R25-Excellence in Cardiovascular Sciences (EICS) program--will continue to provide short-term training for undergraduate students of diverse backgrounds, focusing on research training related to the cardiovascular system with an emphasis on teams of investigators involved in translational research. This approach takes advantage of the broad, multidisciplinary cardiovascular research ongoing at Wake Forest School of Medicine (WFSM), with areas of expertise in hypertension, atherosclerosis, diabetes, obesity, and vascular disease. Faculty from the Hypertension & Vascular Research Center, Center for Diabetes Research, Departments of Physiology/Pharmacology, Pathology and Biochemistry, Molecular Medicine Program and Divisions of Medicine and Surgery participate as Research Mentors, many of whom have participated in the program for 15-20 years. New Research Mentors were recruited for the renewal in keeping with the program directors desire to develop mentoring skills in newly appointed or young investigators. The trainees will be minority students, those from disadvantaged backgrounds, or those with disabilities wishing to pursue a biomedical research project. The overall objectives remain to 1) introduce students to biomedical research through hands-on participation in a research project; 2) introduce students to critical scientific evaluatin by participating in a cardiovascular journal club; 3) provide experience in scientific writing and speaking through presentation of the research project as a poster; 4) provide exposure to research faculty, both basic science and clinical; and 5) foster a long-term commitment to pursue a career in the biomedical sciences through an experience that exemplifies the excitement and challenges of clinically relevant investigation. New objectives for the renewal include: 6) providing exposure to diverse career opportunities by bi-weekly faculty chats with Career Mentors; 7) facilitating matriculation into biomedical graduate programs by providing information on applying to graduate school, taking the GRE examination; and 8) yearly in-depth formal evaluation of the mentees by their Research Mentors. Over 80% of former participants in the program who have finished their undergraduate degrees go on to graduate, medical or industrial technical positions. Furthermore, ~15% of the participants have continued their association with WFSM as PhD students, medical students or technical/post-bac students. In fact, ~30% of the PhD's awarded to under-represented minority students in our biomedical sciences programs from 2009-2011 were from the EICS program. These statistics demonstrate the continued success of the EICS program and its primary focus of providing training to under-represented minorities to facilitate their matriculation into post-graduate programs and their careers in biomedical research. (End of Abstract)
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0.96 |
2003 — 2005 |
Diz, Debra I. |
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.) |
Multianalyte Assays For Cardiovascular Disease @ Wake Forest University Health Sciences
[unreadable] DESCRIPTION (provided by applicant): [unreadable] The RAAS is targeted in therapies that reduce mortality. However, increasing evidence suggests that improvement is independent of reductions in blood pressure or changes in angiotensin II. In fact, a strong link between an activated RAAS and cytokine and other inflammation markers is becoming more apparent as an initiating factor in early hypertension, atherosclerosis and diabetes. Thus, better understanding of the entire RAAS as well as a more extensive complement of other hormonal systems interacting to control blood pressure and influence target organ damage is needed. At present, full assessment of the hormonal systems involved is difficult and costly, in terms of volume of sample and expense of the multiple assays required. Thus, our desire to understand complex interactions among RAAS and associated systems in cardiovascular (CV) pathology has driven us to consider new technologies. The goal of this proposal is to develop new tools for unified assessment of these important hormonal systems, based on the premise that we adapt conventional ELISAs and radioimmunoassays for use with a new technology, the Luminex LabMAP system. This will reduce sample volumes required for multiple individual assays and ultimately reduce complexity and cost of assessing multiple systems. In addition to quantitative assays, we will develop semi-quantitative protein suspension microarrays using the same particle based technology to expedite verification of gene arrays and other molecular techniques that document patterns of activation or inhibition of mechanisms involved in CV disease. We anticipate that application of the new technology will simplify assessment of RAAS and other associated hormonal systems activated synchronously or in opposition. In addition, reduced sample volumes and costs should also allow expansion of both clinical and basic science studies to include more realistic assessment of major hormonal systems involved in CV disease. Finally, an advantage is that it requires relatively inexpensive instrumentation, and provides greater flexibility, quantification, and sensitivity compared with fixed platform protein arrays currently available. As such the peptide and protein applications developed in this proposal will be ideal for widespread use. [unreadable] [unreadable]
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0.96 |
2004 — 2008 |
Diz, Debra I. |
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. |
Aging, the Baroreflex and Ang-(1-7) Receptors @ Wake Forest University Health Sciences
Aging is typified by progressive impairments in cardiovascular regulation that may include increased sympathetic outflow, reduced vagal activity and reduced vascular distensibility. These cardiovascular changes are also associated with decreased activity of the renin-angiotensin (Ang) system (RAS) and insulin resistance. The over-arching goal of Project 4 is to define how insulin and specific components of the RAS act together as major contributors to altered cardiovascular regulation that ultimately lead to elevated systolic pressure and exacerbation of hyperinsulinemia and hyperglycemia during the course of aging. We focus on the opposing actions of Ang II and Ang-(1-7) in the nucleus of the solitary tract (nTS) to modulate the baroreceptor reflex control of sympathetic and parasympathetic outflow. The investigations will define how insulin may act in concert with or opposition to these two peptides in neural regulation of autonomic outflow via actions at cardiovascular relevant regions of the medulla oblongata and hypothalamus. Our experimental strategy will draw upon the combined expertise of members of the Project to define the neural systems, peptide receptor pathways, and metabolic components that interact to account for modification of cardiovascular regulation during aging. Specific Aim 1 investigates the hypothesis that the role of endogenous Ang-(1-7) to facilitate baroreceptor reflex function diminishes with aging, such that the effects of Ang II and insulin are unopposed, thereby contributing to reduced cardiac vagal outflow, enhanced sympathetic outflow, and hypertension. Experiments will focus on the nTS, paraventricular nucleus of the hypothalamus, and rostral ventrolateral medulla as key sites in the brain where actions of Ang peptides and insulin change during the aging process. As one mechanism contributing to the altered roles of Ang peptides and insulin during aging Specific Aim 2 will test the hypothesis that Ang-(1-7) in brain tissue diminishes with age, leading to a shift in the function or expression of Ang II and insulin. Since receptors constitute a key functional component in the aforementioned central regulation of cardiovascular function during aging, Specific Aim 3 will assess the hypothesis that Ang II and Ang-(1-7) receptors undergo a dynamic regulation, in part, determined by alterations in the tissue levels of these two peptides. In particular, the proposed experiments will establish the functional interactions that develop between the AT1b receptor and the mas orphan receptor as key elements responsive to Ang-(1-7). The proposed experiments utilize a transgenic rat model deficient in the production of brain angiotensinogen (ASrAogen), which we show does NOT exhibit cardiovascular impairments over the same time frame typically associated with aging in Sprague-Dawley rats.
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0.96 |
2009 |
Diz, Debra I |
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. |
Brain Ang-(1-7)Vs. Ang Ii: Arterial Pressure, Baroreflex and Metabolic Control @ Wake Forest University Health Sciences
Accounting; Acute; Address; age related; Aging; Angiotensinogen; Animals; Antibodies; Attenuated; Baroreflex; Blood Circulation; Body Weight; Brain; brain pathway; Cell Nucleus; Chimeric Proteins; Control Animal; Dorsal; Down-Regulation; Figs - dietary; Funding; Gene Transfer; Generations; Heart Rate; Hormones; Hypertension; Hypothalamic structure; Immunoglobulin G; Impairment; improved; indexing; Insulin; insulin sensitivity; interest; Intervention; kinase inhibitor; Leptin; Leptin resistance; Long-Term Effects; Longevity; MAP Kinase Kinase 3; Mediating; Metabolic; Metabolic Control; Neuroglia; Neuromodulator; Neurons; Nucleus solitarius; Pathway interactions; Peptides; Peripheral; Phosphoric Monoester Hydrolases; Phosphotransferases; Plasmids; pressure; Principal Investigator; Protein Tyrosine Phosphatase; Rattus; Regulation; Renin-Angiotensin System; Reporting; response; Rest; Role; Signal Pathway; Signal Transduction; Source; Specificity; Sprague-Dawley Rats; Tissues; Transgenic Organisms; Up-Regulation (Physiology)
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0.96 |
2009 — 2012 |
Diz, Debra I. |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Post Baccalaureate Research Education Program (Prep) @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): This program is designed to provide interim positions for under-represented minority students and students from disadvantaged groups with post- baccalaureate degrees interested in pursuing graduate education. The focus is on research training under a strong research mentor who will provide a supportive laboratory environment to develop the trainee's potential for a career in biomedical research. The Program Director will work with trainees for assignment to mentors according to their stated interests and interviews with faculty they select. Recruitment will be by visiting area minority institutions, national mailings and attendance at national minority conferences, a web site, and contact with students involved in other research training programs at the institution. The program takes advantage of broad, multidisciplinary research activities at Wake Forest University School of Medicine (WFUSM) and the commitment of the Dean of the Graduate School of Arts &Sciences to increase diversity. Goals and objectives: 1) increase the number of minority students entering graduate programs at WFUSM from 13% to 18% over five years;2) maintain retention of minority graduate students comparable to majority students;3) increase GRE scores of participants to increase their credentials for graduate programs;and 4) have 100% of the participants apply, 75% enter a PhD or MD/PhD program and 60% enter programs at WFUSM. The program includes the opportunity for coursework to strengthen the academic scientific background, based on area of interest and prior strengths and weaknesses. Other courses/information will be provided to improve GRE scores, introduce responsible conduct of science, improve application and resume preparation, and inform on biomedical graduate programs at WFUSM in particular and graduate education in general. We will introduce biomedical research via hands-on participation in a research project and critical scientific evaluation and presentation of journal articles by participation in a journal club. Scientific writing and speaking is developed by writing abstracts and presentation of the research project as a slide and poster presentation each year at the PREP Symposium and lecture. Students will be exposed to research faculty, both basic science and clinical, to foster a long-term commitment to pursue a career in the biomedical sciences through an experience that exemplifies the excitement and challenges of research. Evaluation by students, including former participants, and mentors will be performed annually. This program is a post-baccalaureate research training program designed to provide interim positions for under-represented minority students and students from disadvantaged groups to participate in research projects and academic skills develop to encourage entry into a PhD program.
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0.96 |
2010 — 2013 |
Diz, Debra I |
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. |
Brain Ang-(1-7) Vs. Ang Ii: Arterial Pressure, Baroreflex and Metabolic Control @ Wake Forest University Health Sciences
Abstract: Our studies in the previous funding period showed that both aging and hypertension are associated with a functional deficiency of Ang-(1-7) within the nucleus of the solitary tract (nTS) accompanying the increase in resting mean arterial pressure (MAP) and impairment of baroreceptor reflex sensitivity (BRS) for control of heart rate. Moreover, we provided evidence that long-term alterations of the brain renin-angiotensin system (RAS) impact not only MAP and BRS, but also metabolic function (leptin, insulin and body weight) over the lifespan in rats. The effects of aging and hypertension may be related to differential regulation of specific cellular sources (neurons vs. glia) of Ang II and Ang-(1-7). Preliminary studies suggest that differences in precursor pathways may also exist, since a highly selective antibody to Ang-(1-12) [Anti-Ang-(1-12) IgG] given intracerebroventricularly lowers MAP in (mRen2)27 transgenic rats. Aim 1 will determine if long-term selective blockade of brain Ang II vs Ang-(1-7), including blockade of potentially different cellular sources or precursors, has divergent actions on MAP, BRS and metabolic function in hypertension and aging. Ang II, insulin and leptin share signaling pathways including phosphoinositol 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK). Protein tyrosine phosphatase (PTP) 1b and dual specificity phosphatases (DUSP-1) are known negative modulators of the kinase pathways, decreasing functional responses to Ang II, leptin and insulin in a variety of settings. We discovered that inhibitors of PI3K lower MAP and improve BRS in (mRen2)27 hypertensive rats, but not Sprague-Dawley (SD) rats. Preliminary data show that inhibition of PTP1 b impairs BRS in SD rats, suggesting that in healthy animals, the PTP1 b provides a positive influence on reflex function. Gene transfer of Ang-(1-7) via fusion-protein-containing plasmid in (mRen2)27 rats with high Ang II and low Ang-(1-7) in the medulla, increases expression of PTP1b and DUSP-1 in dorsomedial medulla, associated with a reduction in MAP and an improvement in BRS. However, PTP1 b is reported to participate in leptin resistance in brain hypothalamic nuclei; therefore, increases in the activity of this phosphatase by Ang-(1-7) might be expected to impair metabolic function. Aim 2 will now investigate whether (a) MAPK and PI3K pathways and their respective negative modulators, DUSP-1 and PTP1b, are differentially regulated with long-term alterations in the brain or peripheral RAS, and (b) whether the differential regulation contributes to changes in MAP, BRS and metabolic function (effects of insulin and leptin on MAP and BRS) within the nTS. Aim 3 will evaluate the long-term consequences of increases in Ang II or Ang-(1-7), or both, in the circulation on the regulation in brain of components of the RAS and the specific signaling pathways of interest. We propose that Ang-(1-7) counteracts the negative effects of Ang II, insulin and leptin on MAP and BRS via increasing the levels of DUSP1 and PTP1b in the nTS. However, Ang-(1-7) mediated upregulation of the PTP1b signaling pathway may contribute to resistance to leptin in hypothalamic pathways involved in body weight and energy control.
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0.96 |
2014 — 2017 |
Diz, Debra I |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Postbaccalaureate Research Education Program (Prep) @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): Wake Forest School of Medicine (WFSM) PREP will provide post-baccalaureate positions for under-represented minority students and students from disadvantaged/disability (URMDD) groups interested in pursuing a PhD. The focus is on research training under a strong research mentor to provide a supportive laboratory environment to develop the trainee's potential for a career in biomedical research. In addition to the research experience, the program includes opportunities for graduate level coursework to strengthen academic scientific background; GRE exam preparation; training in the responsible conduct of research; seminars for developing successful graduate school applications, and resume preparation; training in effective scientific writing and presentations; exposure to non-traditional career paths with a PhD or combined degree; and multi- tiered career counseling and mentoring. Recruitment is by visiting area minority institutions, national mailings, attendance at national conferences, a program web site, contact with students involved in pipeline training programs, involvement of former PREP trainees, significant input from the Graduate School of Arts & Sciences by providing URMDD who are not accepted into PhD programs with information on the PREP, and by hosting special recruitment activities for HBCUs and other diversity initiatives. The program takes advantage of broad, multidisciplinary research activities at WFSM and the support and commitment of the deans towards increasing diversity to attract prospective participants. The PREP Scholars accounted for 29% of the URMDD PhDs awarded in biomedical sciences at WFSM over the past 4 years. PREP trainees have an overall 76% rate of entry into graduate and professional programs, with an entry rate of 56% in PhD programs alone. Retention of PREP Scholars is 90% in PhD programs and 100% in professional programs. Moreover, 100% of PREP trainees obtaining a PhD held T32 positions or individual fellowships, and 76% entered post-doctoral training following the PhD. The goals and objectives of the program are to: 1) increase URMDD student admission into PhD programs nationally and institutionally by having >90% of PREP Scholars apply to PhD programs (currently at 91%), 75% enroll in PhD programs (56% to date), and 50% enroll in PhD programs at WFSM (currently 39%); 2) maintain retention of minority graduate students at or above that of the graduate school as a whole; and 3) have 100% of PREP students take the GRE; provide access to GRE preparatory training to reach minimal standards (~1000) to increase credentials for acceptance into PhD programs. Program evaluation by students (including former participants), mentors, and an internal advisory committee will occur annually, with an external expert review every 2 years, in order to fine-tune programmatic activities to achieve program goals.
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0.96 |
2019 — 2021 |
Brinkley, Tina E Diz, Debra I |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Enhancing Undergraduate Education and Research in Aging to Eliminate Health Disparities (Engaged) @ Wake Forest University Health Sciences
The Enhancing UNderGraduate Education and Research in AGing to Eliminate Health Disparities (ENGAGED) program will address the clear need to increase the diversity of biomedical scientists involved in aging research and the dearth of under-represented (UR) trainees in graduate programs in the biomedical sciences, particularly in aging-related fields. Given the strengths in research on aging at Wake Forest School of Medicine (WFSM) and in the existing didactic training in gerontology and aging-related topics at Wake Forest University (WFU) and Winston-Salem State University (WSSU), the ENGAGED Program Faculty (including Program Directors at WFSM, Co-Directors at WFU and WSSU) has vast academic and professional experiences; a history of collaborations for diversity-focused research and training programs; basic, clinical, population and translational research expertise and funding; and training program administration expertise. Thus, we are particularly well-positioned to offer training for undergraduate UR students to promote greater interest, exposure, and research experiences in the science of aging and health disparities in aging. The goals are to (1) increase awareness of the unique health care issues facing a diverse aging population and of the opportunities for research that addresses these issues and (2) expand opportunities for hands-on paid research internships at WFSM, WFU and WSSU during the academic year and during an 8-9 week summer session. These goals will be accomplished by ?gerontologizing? freshman seminars and introductory health science courses with lectures on topics relevant to aging; creating an ?ENGAGED Research Club? to foster a sense of community around the science of aging; providing a variety of educational activities, including field trips to research laboratories and geriatric clinics, real-world learning experiences in geriatric assessments and laboratory procedures, relevant workshops, seminars and journal clubs; and tracking trainee and program outcomes. Research internships will be offered under the direction of a diverse group of Research Mentors with expertise in cancer, cardiovascular disease, diabetes/obesity, kidney function/disease, neuroscience, and physical function, offering trainees a wide variety of research opportunities in the field of aging. A network of Research and Career Mentors will provide formal and informal resources and counseling on career paths in age-related biomedical research, particularly PhD/advanced degrees, during and after the program. Of note, ~40% of training faculty are UR minorities, and many have research expertise and/or clinical experience addressing health disparities in aging populations. In sum, the proposed ENGAGED program offers several innovative approaches to preparing UR students for a career in research in the field of aging and takes advantage of unique strengths, existing infrastructure, and long-standing collaborations among diverse faculty at WFSM, WFU, and WSSU to ensure successful creation and implementation of the program. Sustainability past NIA funding is anticipated once courses are established and successful outcomes for trainees are evident.
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