Brian Clark - US grants
Affiliations: | Psychology | University of Oregon, Eugene, OR, United States |
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Brian Clark is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1979 — 1982 | Canter, Karl (co-PI) [⬀] Clark, Brian Berko, Stephan [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ Brandeis University |
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1992 — 1996 | Clark, Brian Cope, Timothy |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Transmission of Spike Train Codes Across Spinal Synapses @ Pennsylvania College of Podiatric Medicine |
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2008 — 2010 | Clark, Brian Dean | F30Activity Code Description: Individual fellowships for predoctoral training which leads to the combined M.D./Ph.D. degrees. |
Functional Roles of Kv1 Channels in Inhibitory Cortical Interneurons @ New York University School of Medicine DESCRIPTION (provided by applicant): The long-term objective of this application is to understand how specific types of ion channels contribute to the physiology of cortical neurons and by doing so provide possible insights into how dysfunction of specific ion channels leads to diseases such as epilepsy. This proposal is focused on the Kv1 subfamily of voltagegated potassium channels in a prominent class of neocortical inhibitory interneurons called fast-spiking (FS) cells. FS cells are the most prominent source of inhibition in the cortex. These cells have important roles in regulating excitation in the cortex. Moreover, dysfunction in these cells has been associated with a number of pathologies such as epilepsy and schizophrenia. Mutations in Kv1 proteins such as Kv1.1 are associated with neuropathology and epilepsy in humans. Removal of the Kv1.1 gene in the mouse produces profound epilepsy, however, the cellular basis of this phenotype is not understood. Findings are presented here that show that Kv1.1 protein in the cortex is most prominently expressed in FS interneurons, and Kv1.1- containing channels have a critical role in the regulation of activity in these cells. Understanding the functional roles of Kv1 channels in this important class of inhibitory interneurons is therefore required to elucidate the possible contribution of Kv1 channels in these cells to hyperexcitability and epilepsy. Two specific aims are proposed in order to characterize the contribution of Kv1 channels to the physiology of FS cells. The first is to determine the functional role of Kv1 channels in regulating action potential generation in FS cells. This will be accomplished by recording from FS cells in brain slices and using pharmacological and genetic approaches to isolate the contribution of Kv1 channels to their excitability. The second aim is to determine the molecular composition of Kv1-mediated currents by combining immunohistochemistry, Kv1-subunit specific antibodies, and confocal microscopy. These studies are critical in establishing the roles of these channels in regulating inhibition in the cortex. PUBLIC HEALTH RELEVANCE: Epilepsy affects over three million Americans and thus represents a significant impact to public health. The goal of this study is to understand the normal physiological role of a specific subfamily of proteins that when mutated can produce epilepsy. This research focuses on the role of these proteins in inhibitory cells in the cortex and is a contribution to understanding the pathophysiology of epilepsy in humans. |
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2010 — 2011 | Clark, Brian C | R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Intracortical Mechanisms of Muscle Weakness @ Ohio University Athens DESCRIPTION (provided by applicant): Loss of muscle strength (i.e. weakness) associated with aging is a huge problem as it limits physical independence and is a major factor in the development of disability. Many of the changes that accompany the loss of strength with aging coincide with those observed following immobilization. Thus, immobilization is a model that is particularly well suited to examine losses in strength seen in an aging population. Losses of strength are mediated by changes in both muscular (e.g. atrophy) and neural properties (e.g. cortical inhibition). While there have been extensive studies examining muscular properties, little is known regarding the changes in cortical properties associated with the loss of strength. The potential role of cortical mechanisms in mediating strength is supported by the known effects of motor imagery on increasing strength. More specifically, intracortical facilitation and inhibition may be important neural mechanisms in mediating strength. Intracortical facilitation and inhibition is assessed using paired-pulse transcranial magnetic stimulation, and our pilot data suggests that both aging and immobilization increases long-interval intracortical inhibition (LICI) and the immobilization-induced increase in LICI is associated with the loss of strength. Our central hypothesis is that a high level of LICI is an important neurophysiologic determinant of muscle strength. We will test this hypothesis by accomplishing the following three specific aims: 1) to determine the association between the immobilization-induced changes in intracortical properties and the reduction in muscle strength and central activation;2) to evaluate the effect of motor imagery training on minimizing the immobilization-induced changes in intracortical properties and the reduction in muscle strength and central activation;and 3) to compare differences in intracortical properties between young adults, older healthy adults, and prefrail older adults, and evaluate the interrelationship between age-related differences in intracortical properties and muscle strength and central activation. Understanding the specific neural mechanisms underlying the loss of muscle strength is critical to improving rehabilitation strategies. PUBLIC HEALTH RELEVANCE: Muscle weakness is a common clinical phenomena observed in association with aging and disuse, weakness is associated with disability development, reduced functional capacity, and even mortality. This research will identify the intracortical facilitatory and inhibitory properties in mediating the loss of strength associated with both immobilization and aging. Developing an understanding of the neural mechanisms mediating muscle weakness will contribute to the development of interventions to promote muscle function. |
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2012 — 2013 | Clark, Brian Mcintosh, Susan [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Doctoral Dissertation Improvement Grant: Archaeological Investigations At Genta Mariam @ William Marsh Rice University Under the supervision of Dr. Susan McIntosh, Brian Clark will conduct dissertation research including surveys and excavations around the historically significant 13th-century church of Geneta Mariam in north-central Ethiopia. As in many present day nations, especially in the developing world, religion plays an important role related to governance and centers of power and influence may shift over time. This project is significant because it examines in detail one such system which served to preserve social stability within a traditional society for an extended period. |
0.951 |
2012 — 2016 | Clark, Brian C Thomas, James S [⬀] |
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. |
@ Ohio University Athens Revised Abstract: This application is in response to program announcement PA-10-209 ¿Biology of Manual Therapies.¿ The NIH has recognized that low back pain (LBP) is a significant health problem and that there is a tremendous lack of mechanistic studies on one of the most popular treatments for this disorder (i.e., manipulation treatment). Back pain has a staggeringly negative impact on our society in terms of medical expenses, disability, and individual suffering. According to a recent national survey, more than 18 million Americans over the age of 18 years received manipulative therapies in 2007 at a total annual out of pocket cost of $3.9 billion. Spinal manipulative treatments can be broadly classified as manipulation-based or mobilization-based techniques. Manipulation-based techniques (e.g., translatory thrust) apply a high-velocity, low-amplitude force to the spine and are often accompanied by an audible sound from one or more joints. In contrast, mobilization-based techniques (e.g., muscle energy) use a low-velocity, low-force approach that generally does not produce audible joint sounds. While there is growing evidence for the clinical effectiveness of manipulative therapies to treat low back pain, little is known on the physiologic consequences and effects of either manipulation-based or mobilization-based treatments. Further, addition data are needed to understand how these different manual therapy techniques effect clinical changes in pain and disability. Accordingly, we propose an investigator-blinded, sham-controlled study to test the mechanisms and effectiveness of two manual therapy techniques applied to individuals with chronic low back pain. Specifically, the RELIEF Study (Researching the Effectiveness of Lumbar Interventions for Enhancing Function Study) is an exploratory Phase II randomized clinical trial (RCT) with a nested mechanistic design. As such, there are two major goals of this study. One is to determine the biological mechanisms of these two manual therapy interventions commonly used in the treatment of chronic low back pain. The second is to conduct an exploratory RCT determine the effectiveness of these two manual therapies at reducing pain and disability in patients with chronic low back pain compared to each other as well as a sham control group. Participants with chronic low back pain will be randomly assigned to one of the three treatment arms: 1) spinal manipulation, 2) spinal mobilization, or 3) sham ultrasound therapy (n=54/treatment arm). Treatments will be delivered twice per week for 3-weeks. Within each treatment arm, study participants will be randomly assigned to one of three physiological outcome groups to determine the muscular, spinal, and cortical effects of manual therapies. Treatment interventions will be delivered twice per week for 3-weeks. Participants will be assessed at baseline, immediately after their initial treatment intervention, 48 hours, and 1 month after the last treatment intervention. The proposed experiments will provide a systematic assessment of the muscular, spinal, and cortical mechanisms of two of the most popular manual therapies for the treatment of LBP within an exploratory Phase II RCT design. |
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2014 — 2015 | Clark, Brian C | 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.) |
Novel Exercise Interventions to Improve Trunk Muscle Function: a Pilot Study @ Ohio University Athens DESCRIPTION (provided by applicant): Low back pain (LBP) has a staggeringly negative impact on society in terms of medical expenses and disability. Acute occurrence of LBP results in rapid onset of atrophy of the multifidus muscle, and recurrent LBP is associated with even greater maladaptive changes in trunk extensor muscle morphology and function (i.e., decreased size, strength, and endurance). Rehabilitation strategies for LBP often include resistance training to address these changes in the trunk extensor muscles; however, these exercise protocols are only modestly effective in promoting trunk extensor muscle adaptation as they are generally performed at low-loads (e.g., 25% max strength) that are well below those recommended for muscle adaption (>70% max strength). The use of higher-load trunk exercise is commonly contraindicated because of concern that high spinal compressive loads can cause further injury to the spine. Thus, it is critical to develop therapeutic approaches utilizing low mechanical loads that can still deliver sufficient stimuli to the trunk extensor muscles and reverse the changes in trunk extensor muscle function commonly observed in patients with LBP. Low-load resistance exercise with blood flow restriction (BFR) is an innovative approach for exactly this purpose. This paradigm involves performing exercise with low loads while blood flow to the working muscles is partially occluded by a pressure cuff. We have previously shown that a single bout of BFR exercise increases circulating endocrine growth factors, and we recently completed preliminary studies on chronic BFR exercise training and observed that this modality enhances muscle function without negatively impacting indices of arterial stiffness, nerve conduction, inflammation, and blood coagulation. While this exercise modality cannot be applied directly to the trunk (unfeasible to restrict thorax blood flow), our pilot data indicate a unique cross-transfer effect to the erector spinae muscles when low-load trunk extensor exercise is performed after BFR exercise with the appendicular muscles. Thus performing exercise with the appendicular muscles under BFR prior to low-load exercise with the trunk muscles could enhance muscle size and function without high spinal compressive loads. In this application we propose to conduct an exploratory trial as it relates to determining the effects BFR exercise on erector spinae muscle morphometry and function in patients with recurrent LBP. Our central hypothesis is that BFR exercise with the appendicular muscles performed prior to low-load trunk extensor exercise will produce systemic effects that enhance increases in trunk extensor size, strength, and endurance beyond those seen with only low-load trunk extensor exercise. The potential impact of this work is clear: If effective, this novel exercise modality will provide the foundation for a cost-effective and easy-to-implement rehabilitation strategy that is superior to existing paradigms in its capacity to induce muscle adaptation in the absence of high mechanical and compressive loading on the spine. |
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2014 — 2016 | Clark, Brian S [⬀] | 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. |
Regulation of Retinal Progenitor Cell Competence by Long Noncoding Rnas @ Johns Hopkins University DESCRIPTION (provided by applicant): The generation of neuronal subtype diversity is controlled by the progression of multi-potent neural progenitors through a series of developmental competence states in which they successively lose and often also acquire the ability to generate different cell types. Recent studies have clearly shown that retinal progenitor cell (RPC) competence is controlled cell autonomously, with competence changes hypothesized to occur by temporally dynamic regulation of transcription factor activity. Despite extensive RNA expression profiling of the developing mouse retina, only a few RPC-expressed transcription factors have been identified whose expression tracks with changes in developmental competence. This suggests that other genes that regulate transcription factor activity may ultimately play a central role in regulating RPC competence. The mouse genome contains over 10,000 long noncoding RNAs (lncRNAs), some of which are known to regulate transcription factor activity. Using RNA-Seq analysis, we have identified over 100 lncRNAs that are differentially expressed between early and late-stage RPCs, and we hypothesize that a subset of these will play a critical role in regulating RPC competence. To test this hypothesis, evolutionarily conserved, lncRNAs that display dynamic expression within progenitors have been identified from mouse retinas. Cellular expression patterns of candidate lncRNAs in developing retina will be examined through in situ hybridization and quantitative RT-PCR experiments. The role of candidate lncRNAs in regulation of RPC competence will then be tested using both overexpression and knockdown in developing retina and genetic approaches. Finally, to determine the molecular mechanism by which lncRNAs regulate RPC competence, we will use protein microarrays and RNA immunoprecipitation to identify proteins that directly interact with candidate lncRNAs, and in turn determine whether overexpression or knockdown of these protein-coding genes regulates RPC competence. These studies will improve our understanding of long noncoding RNA function and provide important insight into mechanisms regulating neural progenitor competence. Furthermore, since approximately one-third of all phenotype-associated polymorphisms identified in genome-wide association studies map to non-protein coding regions of the genome, further characterization of lncRNA function may prove critical in understanding the pathology of multiple genetic diseases. |
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2014 — 2018 | Clark, Brian C | 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. |
Neural Mechanisms of Dynapenia @ Ohio University Athens PROJECT SUMMARY A loss of voluntary muscle strength predisposes elders to a 4-fold increase in functional limitations and a 2-fold increase in mortality. For decades, the loss of strength in aging has been largely attributed to the loss of muscle mass. However, recent findings clearly demonstrate that muscle size plays a relatively minor role, and our preliminary data suggests that weak elders activate a substantially smaller proportion of their total muscle during a maximal strength task in comparison to their stronger age-matched counterparts. Despite the significance of maintaining physical strength in aging, virtually all of the research on this topic has focused exclusively on maintaining muscle mass, and little is known regarding the neural mechanisms of weakness. We hypothesize that dynapenic elders have a decreased ability to voluntarily (neurologically) activate skeletal muscle maximally due to increased intracortical inhibition. To test our hypothesis we will conduct a case-control study on dynapenic (i.e., weak) and non-dynapenic elders (n=50/group; >65 yrs). Additionally, the dynapenic individuals will be randomly assigned to one of two interventions (motor imagery (MI) or unilateral resistance exercise (URE) training) to provide an experimental manipulation to increase strength and VA, which will permit us to better elucidate physiological mechanisms. This project will address three specific aims. The first is to determine whether dynapenic elders exhibit differences in knee extensor voluntary activation (VA) in comparison to non-dynapenic elders. The second is to determine whether dynapenic elders exhibit differences in intracortical excitability (assessed via paired-pulse transcranial magnetic stimulation) of the quadriceps femoris muscles in comparison to non-dynapenic elders, and to examine the association between measures of intracortical excitability and VA. The last is to determine the association between the changes in strength, VA, and intracortical excitability induced by motor imagery training and unilateral resistance exercise training in dynapenic individuals. MI of strong muscle contractions has been shown to enhance strength and VA. URE training has also been shown to enhance strength and VA in both the trained and untrained limbs. We will use these interventions as manipulations to enhance strength and VA. This will allow us to better elucidate the mechanistic role of intracortical excitability by examining the association/disassociation between the respective outcomes. While not part of the specific aims per se, we will obtain a number of additional outcomes to characterize the participants, serve as covariates, and use for secondary analyses (e.g., muscle size via MRI, muscle fatigue, white matter hyperintensity, physical activity, electrically-stimulated contractile properties, physical performance, trait and state measures related to exercise, etc.). The proposed work will provide evidence that weakness in the elderly is associated with impairments in VA and will provide insight on the neural mechanisms of this impairment. Collectively, this knowledge will guide the development of targeted strategies to ameliorate weakness and enhance physical function in seniors. |
0.908 |
2016 | Clark, Brian C Thomas, James S [⬀] |
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. |
The Relief Study: Neuromuscular Mechanisms Underlying Spinal Manipulation Treatments @ Ohio University Athens Revised Abstract: This application is in response to program announcement PA-10-209 ?Biology of Manual Therapies.? The NIH has recognized that low back pain (LBP) is a significant health problem and that there is a tremendous lack of mechanistic studies on one of the most popular treatments for this disorder (i.e., manipulation treatment). Back pain has a staggeringly negative impact on our society in terms of medical expenses, disability, and individual suffering. According to a recent national survey, more than 18 million Americans over the age of 18 years received manipulative therapies in 2007 at a total annual out of pocket cost of $3.9 billion. Spinal manipulative treatments can be broadly classified as manipulation-based or mobilization-based techniques. Manipulation-based techniques (e.g., translatory thrust) apply a high-velocity, low-amplitude force to the spine and are often accompanied by an audible sound from one or more joints. In contrast, mobilization-based techniques (e.g., muscle energy) use a low-velocity, low-force approach that generally does not produce audible joint sounds. While there is growing evidence for the clinical effectiveness of manipulative therapies to treat low back pain, little is known on the physiologic consequences and effects of either manipulation-based or mobilization-based treatments. Further, addition data are needed to understand how these different manual therapy techniques effect clinical changes in pain and disability. Accordingly, we propose an investigator-blinded, sham-controlled study to test the mechanisms and effectiveness of two manual therapy techniques applied to individuals with chronic low back pain. Specifically, the RELIEF Study (Researching the Effectiveness of Lumbar Interventions for Enhancing Function Study) is an exploratory Phase II randomized clinical trial (RCT) with a nested mechanistic design. As such, there are two major goals of this study. One is to determine the biological mechanisms of these two manual therapy interventions commonly used in the treatment of chronic low back pain. The second is to conduct an exploratory RCT determine the effectiveness of these two manual therapies at reducing pain and disability in patients with chronic low back pain compared to each other as well as a sham control group. Participants with chronic low back pain will be randomly assigned to one of the three treatment arms: 1) spinal manipulation, 2) spinal mobilization, or 3) sham ultrasound therapy (n=54/treatment arm). Treatments will be delivered twice per week for 3-weeks. Within each treatment arm, study participants will be randomly assigned to one of three physiological outcome groups to determine the muscular, spinal, and cortical effects of manual therapies. Treatment interventions will be delivered twice per week for 3-weeks. Participants will be assessed at baseline, immediately after their initial treatment intervention, 48 hours, and 1 month after the last treatment intervention. The proposed experiments will provide a systematic assessment of the muscular, spinal, and cortical mechanisms of two of the most popular manual therapies for the treatment of LBP within an exploratory Phase II RCT design. |
0.908 |
2016 — 2017 | Clark, Brian C | 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.) |
Innovative Neurophysiological Techniques For Assessing Trunk Muscle Control and Function @ Ohio University Athens GRANT TITLE: Innovative neurophysiological techniques for assessing trunk muscle control and function ABSTRACT Impairments in motor control are linked to low back pain and reductions in physical function in the elderly. Unfortunately, many techniques to assess the neural control of movement are not feasible, or directly applicable, to the trunk musculature. Accordingly, we will develop innovative approaches to study these muscles. Specifically, we will work to develop a reliable, fMRI protocol that investigates the activity of the motor neural networks of selected trunk muscles (specific aim 1). We will also develop a reliable muscle functional MRI (mfMRI) protocol to assess the spatial muscle activation patterns of the deeper lumbopelvic muscles (specific aim 2).We will examine the test-retest reliability of these approaches in four distinct target populations: healthy adults, adults with chronic low back pain, older adults, and older adults with high levels of trunk muscle control (i.e., individuals with expertise in Pilates). By enrolling groups of various levels of trunk muscle control, pathology state and age, we will be able to not only determine the intra-individual reliability, but also the inter-individual reliability as we expect the variability of the measures to be influenced by physical ability, pain state and age. Lastly, in an exploratory aim we will examine the association of our novel neurophysiological measures from Aim 1 and 2 with classic biomechanical and muscle function measures (e.g., trunk extensor strength, trunk extensor force-matching steadiness, and static balance). Successfully developing reliable techniques of this nature will result in new and improved research tools for conducting rigorous studies of therapeutic approaches, such as spinal manipulation and yoga, within the context of trunk muscle control and function. |
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2017 — 2021 | Clark, Brian S [⬀] | K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
@ Washington University The specification of retinal cell types from a common, multi-potent progenitor cell occurs in an overlapping temporal birth order. Previous studies have concluded that the selection of an individual progenitor to undergo a terminal division, whereby at least one daughter cell exits the cell cycle, is largely controlled cell autonomously. Therefore, it has been hypothesized that changes in the ability of retinal progenitors to differentiate as specific retinal cell types results from either an inherent heterogeneity of progenitors resulting in lineage biases or global changes in gene expression across development that correspond to changes in cell fate specification. In order to test these hypotheses, I previously characterized the transcript expression of individual progenitors across retinal development using single-cell RNA-sequencing. These experiments support a model in which retinal progenitors are not lineage restricted but exhibit global changes in gene expression corresponding to progenitor cell maturation across development. Additionally, the profiling of retinal progenitor transcriptomes has enabled us to identify numerous candidate genes hypothesized to 1) regulate the proliferative potential of retinal progenitors 2) confer maturation of retinal progenitors across developmental time and 3) control the temporal specification of individual retinal cell fates. As proof in principal, we showed that the late progenitor cell enriched NFI transcription factors regulate both proliferative quiescence and generation of late-born cell types. The goal of these continued studies is to identify the mechanisms by which retinal progenitor cells are selected to undergo a terminal division and to determine if these candidate genes also impart biases in specification of individual retinal cell fates. The function of candidate genes in the regulation of cell cycle exit and cell fate specification will be determined through gain/loss-of-function experiments within the developing retina through both in vivo and ex vivo electroporations and genetic models. Mechanistic insights into candidate gene function will be performed through protein arrays to identify interacting proteins, ChIRP-seq/ChIP-seq to examine the RNA-DNA or protein-DNA interactions, respectively, and through reporter assays to identify the temporal activity of cis-regulatory elements. These studies will provide import insights into the genes and mechanisms regulating temporal cell fate specification within the developing retina, information vital to understanding the pathogenesis of retinal dystrophies and for understanding treatment of these diseases. |
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2021 | Arnold, William D (co-PI) [⬀] Arnold, William D (co-PI) [⬀] Clark, Brian C Elbasiouny, Sherif M (co-PI) [⬀] |
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. |
Motoneuronal Mechanisms Underlying Age-Related Muscle Weakness @ Ohio University Athens ABSTRACT Forty-two percent of older adults have one or more physical limitations performing daily tasks that are essential for maintaining independence in the community. Age-related weakness is an important contributor to physical impairments, as weakness predisposes older adults to a 4-fold increase in physical limitations. For decades, age-related weakness was largely attributed to the loss of muscle mass, but recent data indicates that mass plays a lesser role than originally thought, highlighting that other neurological and/or muscle quality related factors are critical in the development of weakness. Despite the significance of maintaining physical strength in aging, the majority of the research has focused on maintaining muscle mass. Considerably less is known regarding the neural mechanisms potentially contributing to age-related weakness. This knowledge gap represents a barrier to the development of new interventions to enhance strength and function in older adults. In this application we will test the central hypothesis that age-related weakness is due, in part, to upregulation in motor neuron (MN) SK channels (small conductance calcium-activated potassium channels) that results in type- dependent reductions in intrinsic MN excitability and firing rates. Prior work indicates that aging results in reduced number of MUs (the ?-MN and the muscle fibers that it innervates) and lower firing rates. However, prior work has stopped short of determining whether age-related reductions in MU numbers are related to clinically- meaningful weakness, and determining the ionic mechanisms underlying reduced MN firing rates in aging. In this application we propose a series of parallel, cross-sectional and longitudinal animal (Aims 1 and 2) and human experiments (Aim 3) to test our central hypothesis. Aim 1 will determine if MN excitability dysfunction is involved in age-related weakness and determine its temporal relationship to MU loss in mice. Aim 2 will identify the cellular mechanisms underlying MN excitability dysfunction in aged mice. Aim 3 will determine the role of MN excitability and number in clinically-meaningful, age-related weakness in older adults. This work aligns with stated goals from the National Institute on Aging (NIA). The knowledge to be gained from this work has the potential to fundamentally shift the fields of sarcopenia and frailty research towards MN excitability as an early biomarker for the development of weakness, and identifying key MN ion channels that could serve as a neurotherapeutic targets for treating or preventing age-related weakness. |
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