Bobby Thomas, PhD - US grants
Affiliations: | Neurology | Cornell University, Ithaca, NY, United States |
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High-probability grants
According to our matching algorithm, Bobby Thomas is the likely recipient of the following grants.| Years | Recipients | Code | Title / Keywords | Matching score |
|---|---|---|---|---|
| 2008 — 2012 | Thomas, Bobby | 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. |
Role of Myd88-5 in the Pathogenesis of Parkinson's Disease @ Georgia Regents University DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by widespread neurodegeneration in the brain with profound loss of dopamine-containing neurons of the substantia nigra pars compacta. While majority of PD cases are sporadic, inherited mutations account for approximately 10% of PD cases. Existing evidence implicates a major role for stress activated protein kinases in the pathogenesis of PD. Activation of a neuronal specific c-jun N-terminal kinase-3 (JNK3), followed by recruitment to mitochondria, is associated with irreversible neurodegeneration. The mechanisms underlying this process however remain poorly understood. We have cloned a neuron-specific mitochondrial protein, called MyD88-5, which is enriched in Lewy bodies from brains of postmortem PD patients and in pathologically affected regions of the CNS in a mouse model of 1-synuclein induced PD. We showed that expression of MyD88-5 in vitro led to recruitment of JNK3 from the cytosol to mitochondria and that MyD88-5 knockout mice were resistant to dopaminergic neurodegeneration caused by parkinsonian neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We therefore hypothesize that MyD88-5 may link JNK3 to mitochondria-dependent cell death. Three specific aims are proposed to test this hypothesis. Aim 1 will examine the role of MyD88-5 in activating JNK3 and mediating dopaminergic cell death in MPTP-induced PD using MyD88-5 knockout mice. Aim 2 will examine the role of MyD88-5 in the pathogenesis of mutant human A53T 1-synuclein-induced PD by expressing this transgene in nigral dopaminergic neurons of MyD88-5 knockout mice, or by generating and testing A53T 1- synuclein transgenic/MyD88-5-null mice. Aim 3 will dissect the role of MyD88-5 in modulating basal mitochondrial physiology and function that are important in the PD development in both MPTP- and in 1-synuclein-induced PD using MyD88-5-null mouse. Together, these studies should increase knowledge of MyD88-5-dependent cell damage pathways associated with neurodegeneration in PD and help identify new therapeutic target(s) for the treatment of PD. PUBLIC HEALTH RELEVANCE: This study propose to examine the role of a newly discovered brain mitochondrial protein, MyD88-5, in the onset and development of Parkinson's disease (PD) using the MPTP-neurotoxin and mutant human 1-synuclein mouse models. The study will enrich and refine our understanding of MyD88-5-dependent cell damage pathways observed in PD and identify new target(s) for intervention in PD pathogenesis. |
0.957 |
| 2009 — 2010 | Thomas, Bobby | 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.) |
Activators of Nrf2/Are Pathway as Therapeutic Target For Parkinson's Disease @ Weill Medical Coll of Cornell Univ DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a devastating neurodegenerative movement disorder characterized by a loss of dopamine-containing neurons of substantia nigra, which currently affects about 1.5 million people in the United States. While the causes of PD are unknown, a critical role of oxidative damage and inflammation has been implicated in PD pathogenesis, in that impairment of Nrf2/ARE (NF-E2 related factor 2/antioxidant response element) signaling seems to trigger an irreversible pathway causing oxidative damage, mitochondrial dysfunction and neuroinflammation leading to neurodegeneration. An extremely promising pathway for neurotherapeutics in neurodegenerative diseases is the Nrf2/ARE signaling pathway. The leucine-zipper transcription factor Nrf2 has been identified as a key regulatory factor in the coordinated induction of ARE driven battery of cytoprotective genes, including those encoding for a variety of both antioxidant and anti-inflammatory proteins. We have developed synthetic triterpenoids that are structurally modified to achieve increased bioavailability in the brain and are potent activators of Nrf2/ARE pathway which upregulate large number of genes involved in antioxidant defenses and downregulate genes involved in inflammation. Oral administration of these Nrf2/ARE activators attenuate dopaminergic neurodegeneration caused by parkinsonian neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We hypothesize that these synthetic triterpenoids possess great potential as therapeutic candidates in preventing dopaminergic neurodegeneration in PD. Two specific aims are proposed to test the hypothesis. Aim 1 will examine the relative efficacy of triterpenoid drugs CDDO (2-cyano-3, 12-dioxooleana-1,9-dien-28- oic acid) methylamide, ethylamide, and trifluoroethylamide that activates the Nrf2/ARE pathway, in exerting neuroprotective effects in both acute and chronic MPTP mouse models of PD and will also determine the Nrf2/ARE signaling modulated by these triterpenoid drugs using wild type and Nrf2 knockout mice in an effort to identify their precise mode of neuroprotection. Aim 2 will examine the therapeutic efficacy and Nrf2/ARE signaling as the mode of action of these triterpenoid drugs in blocking mutant human A53T 1-synuclein-induced PD by selectively expressing this transgene in nigral dopaminergic neurons. Testing neuroprotective efficacy of these triterpenoids that upregulate antioxidant genes and downregulate inflammatory genes by activating Nrf2/ARE pathway in the MPTP and 1-synuclein-induced rodent models of PD will enable us to develop these compounds into potential therapeutic drugs to block the death of dopaminergic neurons in Parkinson's disease. PUBLIC HEALTH RELEVANCE: This study proposes to examine the relative efficacy of synthetic triterpenoids that activate the neuroprotective Nrf2/ARE signaling pathway in rescuing dopaminergic neurodegeneration using the MPTP and 1-synuclein mouse model of Parkinson's disease (PD). The study will enable us to identify the best triterpenoid and its mechanism of action that could be used as a potential drug candidate for therapeutic intervention in PD. |
0.934 |
| 2017 — 2018 | Thomas, Bobby | 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. |
Role of Bach1-Mediated Transcriptional Regulation in Neuroprotection @ Augusta University Project Summary Parkinson?s disease (PD) is a progressive, debilitating neurodegenerative disorder with no known cure. While the cause of PD is unknown, oxidative stress, gliosis, excitotoxicity, mitochondrial dysfunction and protein misfolding are all known to play a role in disease pathogenesis. Activation of the Nrf2 pathway is a promising therapeutic approach for PD. Unfortunately, Nrf2-based drugs have relied on electrophilic pharmacophores, which are not tolerated well in patients. A critical barrier to progress in developing more effective Nrf2-based therapies is the current lack of understanding of mechanisms that can safely activate this pathway. Bach1 is a transcription factor that represses Nrf2 gene expression. Our goal is to validate Bach1 inhibition as a novel therapeutic strategy for PD pathogenesis, and to identify new target(s) for intervention. Our central hypothesis is that Bach1 inhibition is neuroprotective in PD due to both Nrf2-dependent and Nrf2-independent mechanisms. This hypothesis is based on the knowledge that genetic deletion and pharmacological inhibition of Bach1 in mice results in constitutive activation of neuroprotective Nrf2-dependent as well as Nrf2-independent genes, and protects against the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our objectives are to 1) determine the cell-specific roles of Bach1 in MPTP neurotoxicity in vivo, 2) delineate the role of Bach1 inhibition in mediating ?-synuclein-induced PD, 3) differentiate between Bach1- and Nrf2- dependent pathways in neuroprotection, and 4) identity novel targets for therapeutic intervention. Our expected outcomes include finding that 1) genetic deletion and pharmacological inhibition of Bach1 ameliorates ?-synucleinopathy and MPTP-neurotoxicity in mice; 2) Bach1-mediated neuroprotective mechanisms involve distinct cell types; 3) Bach1 inhibition or deletion protects Nrf2-null mice against MPTP- neurotoxicity; 4) Bach1-dependent mechanisms of neuroprotection involve upregulation of Nrf2-dependent as well as Nrf2-independent neuroprotective genes, whereas Nrf2-dependent antioxidant response element (ARE)-containing genes are critical for Nrf2-dependent mechanisms. Our studies will impact the field by: 1) improving understanding of Bach1 modulation of signaling pathways and downstream neuroprotective events relevant to pre-clinical models of PD; 2) validating a set of novel, non-electrophilic Bach1 inhibitors as potential therapeutic agents for PD and synucleinopathies; and 3) identifying novel targets for therapeutic intervention. AIM 1: will test the hypothesis that genetic deletion and pharmacological inhibition of Bach1 protects against different modes of nigrostriatal dopaminergic degeneration. AIM 2: will test the hypothesis that Bach1 inhibition attenuates disease development in a mouse model of ?-synucleinopathy. AIM 3: will test the hypothesis that Bach1 inhibition confers neuroprotection via Nrf2-dependent and Nrf2-independent mechanisms. |
0.957 |
| 2019 — 2021 | Thomas, Bobby | 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. |
Role of Bach-1-Mediated Transcriptional Regulation in Neuroprotection @ Medical University of South Carolina Project Summary Parkinson?s disease (PD) is a progressive, debilitating neurodegenerative disorder with no known cure. While the cause of PD is unknown, oxidative stress, gliosis, excitotoxicity, mitochondrial dysfunction and protein misfolding are all known to play a role in disease pathogenesis. Activation of the Nrf2 pathway is a promising therapeutic approach for PD. Unfortunately, Nrf2-based drugs have relied on electrophilic pharmacophores, which are not tolerated well in patients. A critical barrier to progress in developing more effective Nrf2-based therapies is the current lack of understanding of mechanisms that can safely activate this pathway. Bach1 is a transcription factor that represses Nrf2 gene expression. Our goal is to validate Bach1 inhibition as a novel therapeutic strategy for PD pathogenesis, and to identify new target(s) for intervention. Our central hypothesis is that Bach1 inhibition is neuroprotective in PD due to both Nrf2-dependent and Nrf2-independent mechanisms. This hypothesis is based on the knowledge that genetic deletion and pharmacological inhibition of Bach1 in mice results in constitutive activation of neuroprotective Nrf2-dependent as well as Nrf2-independent genes, and protects against the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our objectives are to 1) determine the cell-specific roles of Bach1 in MPTP neurotoxicity in vivo, 2) delineate the role of Bach1 inhibition in mediating ?-synuclein-induced PD, 3) differentiate between Bach1- and Nrf2- dependent pathways in neuroprotection, and 4) identity novel targets for therapeutic intervention. Our expected outcomes include finding that 1) genetic deletion and pharmacological inhibition of Bach1 ameliorates ?-synucleinopathy and MPTP-neurotoxicity in mice; 2) Bach1-mediated neuroprotective mechanisms involve distinct cell types; 3) Bach1 inhibition or deletion protects Nrf2-null mice against MPTP- neurotoxicity; 4) Bach1-dependent mechanisms of neuroprotection involve upregulation of Nrf2-dependent as well as Nrf2-independent neuroprotective genes, whereas Nrf2-dependent antioxidant response element (ARE)-containing genes are critical for Nrf2-dependent mechanisms. Our studies will impact the field by: 1) improving understanding of Bach1 modulation of signaling pathways and downstream neuroprotective events relevant to pre-clinical models of PD; 2) validating a set of novel, non-electrophilic Bach1 inhibitors as potential therapeutic agents for PD and synucleinopathies; and 3) identifying novel targets for therapeutic intervention. AIM 1: will test the hypothesis that genetic deletion and pharmacological inhibition of Bach1 protects against different modes of nigrostriatal dopaminergic degeneration. AIM 2: will test the hypothesis that Bach1 inhibition attenuates disease development in a mouse model of ?-synucleinopathy. AIM 3: will test the hypothesis that Bach1 inhibition confers neuroprotection via Nrf2-dependent and Nrf2-independent mechanisms. |
0.957 |