Frank A. Dinenno, Ph.D. - US grants
Affiliations: | 2000 | University of Colorado, Boulder, Boulder, CO, United States |
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High-probability grants
According to our matching algorithm, Frank A. Dinenno is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2000 — 2002 | Dinenno, Frank A | F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Aging and Alpha-Adrenergic Control of Muscle Blood Flow @ Mayo Clinic Coll of Medicine, Rochester Muscle sympathetic nerve activity (MSNA) plays an important role in the regulation of basal limb vascular tone, as well as regulating limb blood flow during exercise. Resting MSNA increases markedly with age in humans, and recent studies suggest that the vasoconstrictor responses to acute and chronic elevations in MSNA are blunted in older adult humans. Additionally, data regarding sympathetic control of blood flow to contracting skeletal muscle in older adults is lacking. The proposed experiments will determine whether I) the blunted vasoconstriction with age is due to reduced postganglionic alpha-adrenergic receptor responsiveness; 2) the specific alpha-adrenergic receptor subtype contribution to basal and stimulated vascular tone is altered with age; and 3) older adults demonstrate more robust sympathetic vasoconstriction in active skeletal muscle compared with young adults. The strength of the proposed experimental design is that we will target the specific alpha- receptor subtypes before and after abolishing basal sympathetic outflow to the forearm with local anesthetics given at the stellate ganglion. These experiments will provide important new information about sympathetic control of blood flow to resting and contracting skeletal muscle in aging humans. |
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2003 — 2007 | Dinenno, Frank A | K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Aging and Sympathetic Vasoconstriction: Rest Vs Exercise @ Mayo Clinic Coll of Medicine, Rochester DESCRIPTION (provided by applicant): Candidate: The candidate, Frank A. Dinenno, Ph.D., is a physiologist currently supported by an individual NRSA from NIA. Dr. Dinenno's previous and current research focus has been on sympathetic neural control of the circulation, with specific emphasis on how these control mechanisms are modulated by advancing age and regular physical activity in humans. His immediate goal is to acquire new research and professional skills to better prepare and help him achieve his long-term goal of developing a successful independent extramurally-funded research program on aging and cardiovascular function. This proposed KO1 should provide Dr. Dinenno the necessary training to achieve his goal. Career Development Plan: Dr. Dinenno's research career development training activities will consist of (1) acquiring new research skills associated with and complimentary to the proposed research plan; and (2) structured research- and professional skills-related activities. Environment: The environment for Dr. Dinenno's training will be outstanding. The Sponsor (Dr. Joyner) and consulting mentors are engaged in biomedical research and are extramurally-funded from NIH. All are established scientists with strong records of successful mentoring in biomedical research, three of the six are experts in aging research. Support from the General Clinical Research Center will enhance the training environment. Research: The following specific aims will be addressed: 1) to determine whether whole-leg alpha-adrenergic receptor responsiveness is reduced with age under resting conditions in healthy humans, and whether this is specific for cq- or c2-adrenergic receptors; (2) to determine whether the ability to blunt-adrenergic vasoconstriction during large muscle dynamic exercise is impaired in older adults and (3) whether this impairment is due to age-related reductions in nitric oxide bioavailability mediated via elevations in oxidative stress; and (4) to determine whether a program of regular aerobic exercise improves the ability of previously sedentary older adults to blunt sympathetic vasoconstriction at rest and during exercise. The expected results should yield new information regarding sympathetic neural control of the circulation at rest and during exercise in aging humans, and the intervention study should yield novel information about training-induced adaptations and peripheral circulatory control in older adults. |
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2006 — 2007 | Dinenno, Frank 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, Endothelial Dysfunction, and Impaired Vascular Control During Exercise @ Colorado State University-Fort Collins [unreadable] DESCRIPTION (provided by applicant): PROJECT SUMMARY: Aerobic exercise capacity declines progressively with advancing age eventually leading to increased disability, loss of independence, and reduced quality of life in older adults. The overall goal of this research program is to investigate the mechanism(s) involved in the impaired control of muscle blood flow and vascular tone during dynamic exercise in aging humans. This proposal seeks to mechanistically-link oxidative stress-induced peripheral endothelial dysfunction with impaired vascular control during dynamic exercise in aging humans. The general concept is that age-associated increases in oxidative stress reduce endothelium-derived nitric oxide (NO) bioavailability and cause the production of cyclooxygenase-derived vasoconstrictor prostaglandins (PCs), thus impairing local vasodilator responses during exercise in older adults. To test our hypotheses we will address the following specific aims: (1) we will determine whether the impaired control of muscle blood flow and vascular tone observed during dynamic exercise in older adults is due to age-related impairments in endothelium-dependent vasodilation, and specifically, we will determine the independent and interactive contribution of NO and PGs to this impairment; (2) we will determine whether acute reductions in oxidative stress in older adults improves endothelial vasodilator function and therefore, improves muscle blood flow and local vasodilator responses during exercise. The methods employed to address these aims are state-of-the-art and involve local (intra- arterial) administration of various study drugs during exercise to investigate the roles of NO, PGs, and oxidative stress in the control of muscle blood flow in young and older healthy humans. The findings from the proposed studies should provide unique insight into the regulation of muscle blood flow and vascular control during exercise in aging humans, and also could have significant implications for the understanding and treatment of exercise intolerance in diseased populations that also demonstrate endothelial dysfunction (e.g., heart failure patients). RELEVANCE: Aging is associated with a reduced quality of life which is due, in part, to reductions in exercise capacity. The studies in this application are designed to understand the potential contribution of impaired blood vessel function to exercise intolerance in older adults, and will provide ideas on how to prevent or improve this function, thereby enhancing the quality of life of older adults. [unreadable] [unreadable] |
0.967 |
2007 — 2008 | Dinenno, Frank 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.) |
Aging, Endothelial Dysfunction, and Atp-Mediated Vasodilation in Humans @ Colorado State University-Fort Collins [unreadable] DESCRIPTION (provided by applicant): Peripheral vascular endothelial function declines progressively with advancing age in humans, increasing the risk for atherosclerotic and ischemic vascular disease. In addition to its role in maintaining vascular health, the endothelium plays an important role in the regulation of local vascular tone. Recent evidence indicates that the red blood cell (RBC) can act as a "sensor" and releases ATP during mismatches in oxygen demand and delivery, and this ATP can evoke vasodilation and improve local blood flow under such conditions via binding to purinergic (P2y) receptors on the endothelium. Our preliminary data indicates that aging is associated with BB impaired forearm vascular control during specific physiological stressors in which ATP-mediated vasodilation has been documented to be involved. Thus, the overall goal of this research program is to directly test the UU hypothesis that endothelium-dependent ATP-mediated vasodilation is impaired in aging humans, and that this is related to impaired vascular responses during specific physiological stressors. To test our hypothesis we will address the following specific aims: (1) we will determine whether the forearm vasodilator responses to local intra-arterial administration of ATP is impaired in older compared with young healthy adults; and (2) we will determine whether RBC release of ATP during rhythmic handgrip exercise, systemic hypoxia, and combined exercise and systemic hypoxia is reduced with age and relates to impaired forearm vasodilation in older adults. The methods employed to address these aims are state-of-the-art and involve local (intra-arterial) administration of various study drugs at rest, and measurements of forearm venous plasma ATP concentrations in young and older healthy humans during physiological stressors. The findings from the proposed studies should provide unique insight into whether (a) endothelium-dependent ATP-mediated vasodilator responsiveness is reduced with age, (b) whether RBC release of ATP is reduced with age, and (c) whether impairments in both the vascular responsiveness to, and RBC release of, ATP contribute to reduced vasodilator responses during specific physiological stressors that evoke mismatches in oxygen demand and delivery. Our findings could have significant implications for understanding how endothelial dysfunction relates to impaired local vascular control during physiological (e.g., exercise, hypoxia) and pathophysiological (e.g., coronary and cerebrovascular ischemia) conditions in older healthy and diseased humans. Aging is associated with an increased risk for cardiovascular disease. The studies in this application are designed to understand how impaired blood vessel function might contribute to a reduced ability of older adults to respond to conditions in which not enough blood is being delivered to specific tissues, and could provide ideas on how to eventually improve cardiovascular health of older adults. [unreadable] [unreadable] [unreadable] |
0.967 |
2010 — 2011 | Dinenno, Frank 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, Obstructive Sleep Apnea, and Impaired Peripheral Vascular Control During S @ Colorado State University DESCRIPTION (provided by applicant): Peripheral vascular endothelial function declines progressively with advancing age in humans, and is further impaired in patients with obstructive sleep apnea (OSA), increasing the risk for atherosclerotic and ischemic vascular disease. In addition to its role in maintaining vascular health, the endothelium plays an important role in the regulation of local vascular tone. Further, the sympathoadrenal system is a key regulator of vascular tone, particularly during stress conditions in humans. Our preliminary data indicates that healthy aging is associated with impaired peripheral vascular control during acute reductions in arterial oxygen content (hypoxia), a physiological and pathophysiological stress that evokes reflex increases in sympathoadrenal activity as well as the synthesis of local endothelium-derived vasoactive factors. Older OSA patients experience frequent and recurrent systemic hypoxia and are at elevated risk for cardiovascular morbidity and mortality. Thus, the overall goal of this research program is to determine the integrative sympathoadrenal and local endothelium-dependent contributors to vascular tone during hypoxic stress in older healthy subjects and older moderate OSA patients. Our general working hypothesis is that there is an alteration in the balance of sympathoadrenal and endothelium-dependent control of vascular tone which leads to a severely impaired peripheral vasodilatory response in older humans, and that this impairment is even greater in older OSA patients. To test our hypothesis we will address the following specific aims: (1) we will determine the sympathoadrenal and peripheral vascular responses to graded systemic hypoxia in older healthy adults and older moderate OSA patients;(2) we will determine whether local blockade of -adrenergic vasoconstriction and -adrenergic mediated vasodilation reduces the age- and disease-group differences in peripheral vascular responses to graded systemic hypoxia;(3) we will determine whether the impaired peripheral vasodilator responses to systemic hypoxia is due to age- and disease-related reductions in the local contribution of endothelium-derived nitric oxide and prostaglandins to this response, and whether acute improvements in endothelium-dependent vasodilation via ascorbic acid infusion augments local hypoxia- induced vasodilation in older healthy and older OSA humans;and (4) we will determine whether augmented endothelin-1 mediated vasoconstriction limits hypoxic vasodilation in older healthy adults and further limits this response in older OSA patients. The methods employed to address these aims are state-of-the-art and involve direct recordings of sympathetic neural activity and local (intra-arterial) administration of various study drugs to determine the mechanisms underlying this age- and disease-related impairment. The findings from the proposed studies will provide novel insight into the integrative control of peripheral vascular tone during hypoxia in older healthy and diseased adults and could have significant clinical implications for understanding vascular function in related patient populations (e.g., congestive heart failure, ischemic vascular disease). PUBLIC HEALTH RELEVANCE: Older healthy adults and patients with obstructive sleep apnea are at elevated risk for the development of cardiovascular disease. The studies in this application are designed to understand how impairments in the control of blood vessel function might contribute to a reduced ability of older healthy adults and sleep apnea patients to respond to conditions in which not enough blood and oxygen are being delivered to specific tissues, and could provide ideas on how to eventually improve cardiovascular health of older healthy and diseased adults. |
0.979 |
2010 — 2011 | Dinenno, Frank 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.) |
Role of Circulating Atp and Smooth Muscle Cell Hyperpolarization in Vascular Cont @ Colorado State University DESCRIPTION (provided by applicant): The matching of blood flow and oxygen delivery to tissue oxygen demand is one of the most fundamental physiological processes. Recent evidence indicates that the red blood cell can act as a "sensor" and releases ATP during mismatches in oxygen demand and delivery, and this ATP can evoke vasodilation and improve local blood flow under such conditions via binding to purinergic (P2y) receptors on the endothelium. In addition to the direct vasodilatory effect, we have recently demonstrated that ATP is also capable of inhibiting sympathetic vasoconstriction ("sympatholytic"), which could further aid in blood flow and oxygen distribution. Our preliminary data indicates that the forearm vasodilator responses to ATP are not due to breakdown to adenosine, and importantly, are independent of nitric oxide and vasodilating prostaglandins. Thus, the overall goal of this exploratory research program is to directly test the hypothesis that endothelium-dependent ATP- mediated vasodilation is due to vascular smooth muscle cell hyperpolarization in humans, and to further test whether the proposed pathways are involved in vascular control in contracting muscle. To test our hypotheses we will address the following specific aims: (1) we will determine whether the forearm vasodilator responses to local intra-arterial administration of ATP are reduced by individual and combined inhibition of inward rectifying potassium channels (KIR;via barium chloride) and Na+/K+ ATPase activity (via oubain);and (2) we will determine whether the forearm vasodilator responses to graded rhythmic handgrip exercise and the ability of muscle contractions to blunt sympathetic 1-adrenergic receptor mediated vasoconstriction are impaired after inhibition of KIR channels and Na+/K+ ATPase activity in humans. The methods employed to address these aims are state-of-the-art and involve local (intra-arterial) administration of various study drugs at rest and during exercise, and measurements of forearm arterial and venous plasma ATP concentrations in young healthy humans. The findings from the proposed studies should provide unique insight into the mechanisms by which circulating ATP causes local vasodilation, and whether the hypothesized signaling pathways evoking hyperpolarization are involved in vascular control in contracting skeletal muscle. Given that impaired endothelium-dependent vasodilation is a hallmark of patients at risk or whom already exhibit cardiovascular disease, and that ATP release from red blood cells of certain patients (e.g. diabetics) is impaired, our findings regarding the mechanisms underlying ATP-mediated vasodilation could have significant implications for understanding impaired local vascular control during physiological (e.g., exercise, hypoxia) and pathophysiological (e.g., coronary and cerebrovascular ischemia) conditions in older healthy and diseased humans. PUBLIC HEALTH RELEVANCE: The studies outlined in this application are designed to address fundamental questions regarding how blood flow and oxygen delivery are controlled to peripheral tissues in humans. Understanding these basic regulatory mechanisms will provide important information that may stimulate ideas on how to improve regional blood flow and oxygen delivery in patient populations at risk for both acute and chronic cardiovascular complications. |
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2012 — 2013 | Dinenno, Frank 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, Sleep Apnea, and Vascular Control During Systemic Hypoxia @ Colorado State University DESCRIPTION (provided by applicant): Peripheral vascular endothelial function declines progressively with advancing age in humans, and is further impaired in patients with obstructive sleep apnea (OSA), increasing the risk for atherosclerotic and ischemic vascular disease. In addition to its role in maintaining vascular health, the endothelium plays an important role in the regulation of local vascular tone. Further, the sympathoadrenal system is a key regulator of vascular tone, particularly during stress conditions in humans. Our preliminary data indicates that healthy aging is associated with impaired peripheral vascular control during acute reductions in arterial oxygen content (hypoxia), a physiological and pathophysiological stress that evokes reflex increases in sympathoadrenal activity as well as the synthesis of local endothelium-derived vasoactive factors. Older OSA patients experience frequent and recurrent systemic hypoxia and are at elevated risk for cardiovascular morbidity and mortality. Thus, the overall goal of this research program is to determine the integrative sympathoadrenal and local endothelium-dependent contributors to vascular tone during hypoxic stress in older healthy subjects and older moderate OSA patients. Our general working hypothesis is that there is an alteration in the balance of sympathoadrenal and endothelium-dependent control of vascular tone which leads to a severely impaired peripheral vasodilatory response in older humans, and that this impairment is even greater in older OSA patients. To test our hypothesis we will address the following specific aims: (1) we will determine the sympathoadrenal and peripheral vascular responses to graded systemic hypoxia in older healthy adults and older moderate OSA patients; (2) we will determine whether local blockade of -adrenergic vasoconstriction and -adrenergic mediated vasodilation reduces the age- and disease-group differences in peripheral vascular responses to graded systemic hypoxia; (3) we will determine whether the impaired peripheral vasodilator responses to systemic hypoxia is due to age- and disease-related reductions in the local contribution of endothelium-derived nitric oxide and prostaglandins to this response, and whether acute improvements in endothelium-dependent vasodilation via ascorbic acid infusion augments local hypoxia- induced vasodilation in older healthy and older OSA humans; and (4) we will determine whether augmented endothelin-1 mediated vasoconstriction limits hypoxic vasodilation in older healthy adults and further limits this response in older OSA patients. The methods employed to address these aims are state-of-the-art and involve direct recordings of sympathetic neural activity and local (intra-arterial) administration of various study drugs to determine the mechanisms underlying this age- and disease-related impairment. The findings from the proposed studies will provide novel insight into the integrative control of peripheral vascular tone during hypoxia in older healthy and diseased adults and could have significant clinical implications for understanding vascular function in related patient populations (e.g., congestive heart failure, ischemic vascular disease). PUBLIC HEALTH RELEVANCE: Older healthy adults and patients with obstructive sleep apnea are at elevated risk for the development of cardiovascular disease. The studies in this application are designed to understand how impairments in the control of blood vessel function might contribute to a reduced ability of older healthy adults and sleep apnea patients to respond to conditions in which not enough blood and oxygen are being delivered to specific tissues, and could provide ideas on how to eventually improve cardiovascular health of older healthy and diseased adults. |
0.979 |
2014 | Dinenno, Frank 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, Sleep Apnea, & Vascular Control During Systemic Hypoxia @ Colorado State University DESCRIPTION (provided by applicant): Peripheral vascular endothelial function declines progressively with advancing age in humans, and is further impaired in patients with obstructive sleep apnea (OSA), increasing the risk for atherosclerotic and ischemic vascular disease. In addition to its role in maintaining vascular health, the endothelium plays an important role in the regulation of local vascular tone. Further, the sympathoadrenal system is a key regulator of vascular tone, particularly during stress conditions in humans. Our preliminary data indicates that healthy aging is associated with impaired peripheral vascular control during acute reductions in arterial oxygen content (hypoxia), a physiological and pathophysiological stress that evokes reflex increases in sympathoadrenal activity as well as the synthesis of local endothelium-derived vasoactive factors. Older OSA patients experience frequent and recurrent systemic hypoxia and are at elevated risk for cardiovascular morbidity and mortality. Thus, the overall goal of this research program is to determine the integrative sympathoadrenal and local endothelium-dependent contributors to vascular tone during hypoxic stress in older healthy subjects and older moderate OSA patients. Our general working hypothesis is that there is an alteration in the balance of sympathoadrenal and endothelium-dependent control of vascular tone which leads to a severely impaired peripheral vasodilatory response in older humans, and that this impairment is even greater in older OSA patients. To test our hypothesis we will address the following specific aims: (1) we will determine the sympathoadrenal and peripheral vascular responses to graded systemic hypoxia in older healthy adults and older moderate OSA patients; (2) we will determine whether local blockade of -adrenergic vasoconstriction and -adrenergic mediated vasodilation reduces the age- and disease-group differences in peripheral vascular responses to graded systemic hypoxia; (3) we will determine whether the impaired peripheral vasodilator responses to systemic hypoxia is due to age- and disease-related reductions in the local contribution of endothelium-derived nitric oxide and prostaglandins to this response, and whether acute improvements in endothelium-dependent vasodilation via ascorbic acid infusion augments local hypoxia- induced vasodilation in older healthy and older OSA humans; and (4) we will determine whether augmented endothelin-1 mediated vasoconstriction limits hypoxic vasodilation in older healthy adults and further limits this response in older OSA patients. The methods employed to address these aims are state-of-the-art and involve direct recordings of sympathetic neural activity and local (intra-arterial) administration of various study drugs to determine the mechanisms underlying this age- and disease-related impairment. The findings from the proposed studies will provide novel insight into the integrative control of peripheral vascular tone during hypoxia in older healthy and diseased adults and could have significant clinical implications for understanding vascular function in related patient populations (e.g., congestive heart failure, ischemic vascular disease). |
0.979 |
2014 — 2017 | Dinenno, Frank A Joyner, Michael J |
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. |
@ Mayo Clinic Rochester DESCRIPTION (provided by applicant): Exercise hyperemia is a biomedically significant phenomenon because skeletal muscle blood flow is a key determinant of exercise capacity in health and disease. However, the mechanisms governing exercise hyperemia that match muscle blood flow with metabolism remain poorly understood in spite of ongoing investigation since at least the 1870s. Recently, ATP has emerged as a vasodilating factor that might match O2 delivery and metabolic demand in contracting muscles. The idea is that hemoglobin in red blood cells (RBCs) releases ATP as it desaturates to cause dilation in areas of contracting muscle with high levels of O2 demand. This ATP release also opposes sympathetic vasoconstriction (functional sympatholysis) to further facilitate flow/metabolism matching. These observations, plus ATP's potent vasodilator actions, make it an attractive candidate to explain several major features of the exercise hyperemia response. In this context, we seek to understand if: a) ATP mediated vasodilation in contracting skeletal muscle is attenuated during hyperbaric hyperoxia when arterial O2 content is increased by ~25%; b) the vasodilator responses to exercise are less sensitive to changes in arterial O2 content in patients with the ?F508 mutation form of cystic fibrosis whose RBCs lack the ability to release ATP in vitro; and c) if the vasodilator responses to exercise are less sensitive to changes in arterial O2 content in the contracting muscle of healthy older volunteers who may also have altered ATP release from RBCs. In Aim 1 we will determine if ATP release is reduced during exercise with hyperbaric hyperoxia. Skeletal muscle blood flow is reduced by ~25% when arterial O2 content is increased by ~25% with hyperbaric hyperoxia. In Aim 2 we will determine if muscle blood flow is sensitive to changes in arterial O2 content in patients with CF. In Aim 3 we will determine if muscle blood flow is sensitive to changes in arterial O2 content in healthy older subjects. We will also conduct parallel in vitro studies in isolated RBCs as part of a highly mechanistic and translational experimental strategy. Our aims are designed to evaluate the relationships between forearm blood flow, O2 delivery and deep venous ATP responses during handgripping when arterial O2 content is altered by 20-25% using either hyperbaric hyperoxia or normobaric hypoxia. Our approach also leverages our prior experience with hypoxia and hyperbaric hyperoxia, ATP measurements and our history of studies in older humans and patients with CF. Thus, we are proposing innovative and novel approaches to comprehensively test the ATP hypothesis and exercise hyperemia in humans. Our studies also have the potential to identify circulating ATP, and perhaps the red blood cell, as a therapeutic target in disease states that increase with advancing age and are associated with reduced muscle perfusion (e.g. heart failure) or inadequate O2 delivery in other vascular beds. Finally, our proposal is consistent with NHLBI and NIH priorities related to translational research that seek to understand the contribution of mechanisms identified in animal models and in vitro experimental paradigms to humans. |
0.903 |
2018 — 2019 | Dinenno, Frank 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.) |
Pyridoxine, P2 Receptor Antagonism, and Atp-Mediated Vasodilation in Young and Older Adults @ Colorado State University PROJECT SUMMARY: The matching of blood flow and oxygen delivery to tissue oxygen demand is one of the most fundamental physiological processes. Recent evidence indicates that the red blood cell can act as a ?sensor? and releases ATP during mismatches in oxygen demand and delivery, and this ATP can evoke vasodilation and improve local blood flow under such conditions via binding to purinergic (P2) receptors on the endothelium. In addition to the direct vasodilatory effect, we have recently demonstrated that ATP is also capable of inhibiting sympathetic vasoconstriction (?sympatholytic?), which could further aid in blood flow and oxygen distribution. Aging is associated with impaired blood flow and oxygen delivery during conditions of hemoglobin deoxygenation (e.g. hypoxia, exercise), and we have recently demonstrated that this is associated with a lack of increase in circulating ATP due impaired red blood cell ATP release. Currently, the major critical barrier to our mechanistic understanding of how ATP controls vascular tone in humans is the lack of an effective inhibitor of ATP, P2 receptor-mediated vasodilation. Our preliminary data indicates that local intra- arterial infusions of pyridoxine hydrochloride significantly inhibits ATP-mediated vasodilation in young adults. Thus, the overall goal of this exploratory research program is to directly test the hypothesis that pyridoxine hydrochloride is an effective antagonist that inhibits ATP, P2 receptor-mediated vasodilation in humans in vivo, and to directly determine the role of intravascular ATP in the control of blood flow and oxygen delivery in young and older adults during various physiological stimuli. To test our hypotheses we will address the following specific aims. In Specific Aim 1 we will determine whether the forearm vasodilator responses to local intra- arterial administration of ATP are inhibited by local infusions of pyridoxine hydrochloride. We will also determine the specificity of this inhibition to intravascular ATP by administering various endothelium-dependent and -independent agonists, as well as other purines, to rigorously address this aim. In Specific Aim 2 we will determine whether the forearm vasodilator responses to graded systemic hypoxia and graded rhythmic handgrip exercise are reduced after inhibition of P2 receptors in young and older adults. The methods employed to address these aims are state-of-the-art and involve local (intra-arterial) administration of various study drugs at rest and during systemic hypoxia and exercise, and measurements of forearm arterial and venous plasma ATP concentrations in young and older healthy humans. The findings from the proposed studies will establish the efficacy of pyridoxine hydrochloride as a pharmacological inhibitor of P2 receptors in vivo, and will provide the first data regarding the mechanistic role of ATP in vascular control during physiological stress in both young and older adults. This could serve as the impetus for future studies designed to improve circulating ATP and/or P2 receptor signaling in various patient populations suffering from exercise intolerance or tissue ischemia due to impaired local regulation of blood flow and oxygen delivery. |
0.979 |
2018 — 2019 | Dinenno, Frank A Gentile, Christopher L |
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.) |
Targeting Endoplasmic Reticulum Stress in Aging- and Obesity-Induced Vascular Dysfunction @ Colorado State University PROJECT SUMMARY Endoplasmic reticulum (ER) stress has emerged as an important mediator of disease pathology. Over the last decade, hundreds of studies performed in cell culture and experimental animal models have demonstrated that inhibition of ER stress prevents or reverses numerous chronic diseases, including cardiovascular disease (CVD). Aging is the primary risk factor for cardiovascular disease (CVD). One critical process that links aging to CVD is the development of vascular dysfunction, characterized by endothelial dysfunction and arterial stiffness. Both endothelial dysfunction and arterial stiffness predict cardiovascular events in older individuals. Aging often coincides with obesity, another independent risk factor for CVD. Although vascular function is well characterized in both aging and obesity, it?s currently unclear how these two physiological states interact to modulate vascular function, and whether the combination of aging and obesity has additive or compounding effects on endothelial dysfunction and arterial stiffness. Another important question regarding aging and obesity is whether vascular dysfunction is driven by the same underlying cellular mechanisms in both conditions. Accumulating data in experimental animals, including preliminary results in this application, suggest that ER stress may be an important factor in aging- and obesity-related vascular dysfunction. Published data from our laboratory demonstrate that middle-aged and older obese adults with endothelial dysfunction display evidence of ER stress within biopsied endothelial cells. In light of these data, the overall goal of this proposal is to test the hypothesis that ER stress is associated with human vascular dysfunction in the settings of aging and obesity, and to determine the efficacy of the chemical chaperone tauro-ursodeoxycholic acid (TUDCA), an established inhibitor of ER stress, to reduce endothelial cell ER stress and improve vascular function in these at-risk individuals. Aim 1 will determine the relative contributions of aging and obesity on vascular dysfunction and endothelial ER stress in humans. We hypothesize that aging and obesity will have additive effects on vascular dysfunction and ER stress, and that endothelial ER stress will be correlated with vascular dysfunction in the entire cohort. Aim 2 will determine whether 8 weeks of TUDCA administration improves vascular function and ER stress in older lean and obese humans. Our primary hypothesis is that TUDCA reduces endothelial cell ER stress and improves endothelial function and arterial stiffness in older and/or obese individuals . Our secondary hypothesis is that one of the mechanisms by which inhibition of ER stress via TUDCA will improve vascular function is via a reduction in oxidative stress. Results from this study have the potential to identify a novel, safe, and clinically relevant intervention strategy for the treatment of vascular dysfunction in an aging population at high-risk for the development of CVD. |
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