2014 — 2021 |
Zachariou, Venetia |
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. |
Cellular Mechanisms of Antidepressant Drug Actions in Neuropathic Pain Models @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): This project will elucidate antidepressant-induced changes on signal transduction in sensory and affective brain circuitry mediating neuropathic pain. Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the pain-like symptoms of this disorder have low efficacy, carry major side-effects and in the case of opioids may lead to debilitating physical addiction. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants and the selective, serotonin/norepinephrine reuptake inhibitors contain both antiallodynic and antidepressant properties. However, their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that RGS9-2, a potent regulator of striatal GPCR signaling amplitude and desensitization, plays a potent, modulatory role in the antiallodynic and antidepressant actions of TCAs. We will use genetic mouse models and gene transfer approaches to test our hypothesis that RGS9-2 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain models. In addition, we will use biochemical and molecular biological approaches to test our hypotheses on both the critical RGS9-2 protein-protein interactions modulating the effects of TCA and SNRI and the long-term epigenetic changes downstream of RGS9-2 in response to TCA and SNRI treatment. Finally, we will characterize antidepressant-induced and RGS9-2 modulated global gene regulation using RNA-sequencing in models of neuropathic pain. Our findings will clarify the mechanism by which GPCR signaling machinery in NAc modulates the effects of antidepressant drugs on the sensory and affective symptoms of neuropathic pain.
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0.907 |
2015 — 2016 |
Zachariou, Venetia |
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.) |
Hdac5 in the Nucleus Accumbens Modulates the Actions of Antidepressant Drugs in Models of Neuropathic Pain @ Icahn School of Medicine At Mount Sinai
? DESCRIPTION (provided by applicant): Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the painlike symptoms of this disorder have low efficacy, and their therapeutic actions are accompanied by major side effects. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants (TCAs) and the selective, serotonin/norepinephrine reuptake inhibitors (SNRIs) contain both antiallodynic and antidepressant properties. However, they have a slow onset of action, and their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that the enzyme histone deacetylase 5 (HDAC5), which acts as a transcriptional repressor, plays a potent modulatory role in the antiallodynic and antidepressant actions of TCAs. HDAC5 modulates the function of chromatin complexes, but it is also possessing cytoplasmic functions. We will use genetic mouse models and gene transfer approaches to test our hypothesis that HDAC5 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain states. In addition, we will use biochemical approaches to determine the critical HDAC5 protein-protein interactions and phosphorylation events that determine the nucleocytoplasmic shuttling of this molecule. Finally, we will use RNAsequencing to investigate the influence of HDAC5 gene in antidepressant drug induced global gene regulation in the NAc. Our findings will provide important new information on the long-term adaptations involved in the actions of antidepressant medications under neuropathic pain conditions.
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0.907 |
2017 — 2021 |
Zachariou, Venetia |
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. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Animal Models Core @ Icahn School of Medicine At Mount Sinai
PROJECT SUMMARY ? ANIMAL MODELS CORE The Animal Models Core provides a broad range of the most sophisticated mouse models of depression and acute behavioral assays to support the Center's goals to establish epigenetic mechanisms of depression and other stress-related disorders. Such models include several chronic stress paradigms in adult mice as well as paradigms of early life stress, with a focus on comparisons of stress responses in male and female animals across the life cycle. The imperative to employ this broad behavioral battery is that it is difficult to infer something about such a heterogeneous syndrome as depression, about which there is still limited etiologic and pathophysiological information, from a single model or even a limited number of models. The Core then utilizes these models in two main ways. First, the Core provides microdissections of limbic brain regions from carefully defined mouse models for molecular characterization in all four Projects and in the Chromatin and Gene Analysis Core. Second, the Core provides extensive behavioral characterization after manipulation of specific genes of interest to Projects 1 through 4 and is, consequently, instrumental in providing causal, mechanistic data on how specific forms of epigenetic regulation, and the specific target genes affected, influence depression-related behaviors. The Core accomplishes this by analyzing a range of genetic mutant mice as well as by utilizing intra-cerebral injection of viral vectors or of small molecule activators/inhibitors of target proteins. Additionally, the Core is responsible for generating most of the viral vectors used by Project investigators. The Core also collaborates with each of the Projects to employ neurophysiological recording techniques, optogenetic tools, and fiber photometry with in vivo calcium imaging to understanding how stress-induced gene regulation controls the functioning of the affected neurons and their circuits to cause behavioral abnormalities. By consolidating this behavioral, viral vector, and functional work within a centralized Core, we ensure rigorous control over the data and facilitate comparisons and contrasts of experimental results across the individual Projects. This consolidation also makes financial sense, since we concentrate and maximize efficient use of our complementary expertise.
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0.907 |
2017 — 2018 |
Zachariou, Venetia |
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 Hdac6 For the Treatment of Neuropathic Pain @ Icahn School of Medicine At Mount Sinai
HDAC6, a new therapeutic target for chronic pain Chronic neuropathic pain is a severe medical condition and an important unmet medical need. Current first-line medications successfully provide relief in a subset of patients but their activity usually require weeks to months of administration a delay also observed in preclinical models. In contrast, recent preclinical studies show that broad-acting histone deceatylase (HDAC) inhibitors, such as trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA), rapidly relieve hyperalgesia in various models of neuropathic pain. This points to HDAC inhibition as a promising avenue for the development of new treatments. However, the exact mechanisms underlying this rapid analgesic activity remain elusive. Characterizing the specific HDAC isoforms, the HDAC substrates, and brain networks that mediate these analgesic effects, will provide important insights for the design of newer medications with improved side-effect profile. Our preliminary data indicate that the selective pharmacological blockade of HDAC6, a mainly cytoplasmic class IIB isoform, is sufficient to fully recapitulate the analgesic activity of broad acting HDAC inhibitors, even though this isoform does not deacetylate chromatin in vivo. Under Aim I we will combine state of the art isoform-selective pharmacological probes and conditional loss of function of HDAC6 using a floxed HDAC6 allele to investigate the role of HDAC6 in pain- like behaviors associated with peripheral nerve injury. Specifically, we will use the spare nerve model of neuropathic pain to test the hypothesis that HDAC6 activity at certain supraspinal sites, such as the serotonergic Raphe Nuclei (RN), is necessary and sufficient for the development of sensory hypersensitivity and/or depression-like behaviors. Under Aim II, we will track changes in the expression and activity of HDAC6 at successive time-points after the induction of nerve injury. We will also monitor changes in the phosphorylation of HDAC6 and the acetylation of Hsp90 and alpha-tubulin, two validated targets of HDAC6, under neuropathic pain states. Finally, we will assess the impact of HDAC6 in cytokine expression in the RN.
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0.907 |
2019 — 2021 |
Zachariou, Venetia |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
A Female Specific Role of Rgsz1 in Modulation of Chronic Pain @ Icahn School of Medicine At Mount Sinai
SUMMARY While the mechanisms modulating the transmission and perception of chronic pain differ between men and women, the exact neuroanatomical and molecular differences existing between the sexes remain only partly understood. This proposal focuses on the study of intracellular mechanisms that modulate symptoms of long-term pain states in female mice. We have identified signal transduction mechanisms in the mouse ventrolateral periaqueductal gray (vlPAG) that selectively modulate sensory symptoms of inflammatory and neuropathic pain in female mice. The signal transduction modulator Regulator of G Protein Signaling-1 (RGSz1) controls the function of G protein coupled receptors (GPCRs) by binding to activated G?i subunits, including the Golgi enriched G?z. RGSz1 negatively modulates the amplitude and direction of signal transduction of several GPCRs involved in the modulation of pain processing, including the serotonin 5HT1A receptor. We recently found that RGSz1 mRNA and protein levels are dynamically regulated in the vlPAG of female (but not male) mice by long-term peripheral inflammation. Constitutive deletion of the RGSz1 gene or vlPAG-specific knockdown of RGSz1, exacerbate sensory hypersensitivity behaviors such as thermal hyperalgesia and mechanical allodynia in female mice, but they have no effect in male mice. We will investigate the mechanisms regulating the expression of RGSz1 in the male and female vlPAG at various points after the induction of peripheral nerve injury or inflammation. We will apply several genetic mouse models for regional inactivation or overexpression of RGSz1 in vlPAG neuronal subsets, along with brain biochemistry, electrophysiology and voltammetry to understand the sex-specific role of RGSz1 in the function of the descending inhibitory pathway in models of chronic pain. Since RGSz1 plays a prominent role in the function of the Golgi apparatus, will apply chronic pain models to understand the impact of RGSz1 on the expression levels of trans- Golgi components in the presence and in the absence of pain. Finally, we will use RNA Sequencing to understand the impact of RGSz1 on gene expression adaptations underlying chronic pain states.
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0.907 |