2012 — 2014 |
Bosmans, Frank Gert Werner |
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. |
The Influence of Beta-Subunits and Sphingomyelin On Sodium Channel Function @ Johns Hopkins University
Voltage-activated sodium (Nav) channels are found throughout the human body where they form the cornerstones of fast electrical signaling by regulating the Na+ permeability ofthe cell membrane. As such, Nav channels are among the most widely targeted ion channels by both drugs and toxins. Their medical relevance is underscored by mutations that underlie debilitating disorders such as epilepsy, muscle weakness, cardiac arrhythmias and pain syndromes. Despite their physiological importance, our understanding of thes;e channels is hampered by a lack of insight into their complex structures and working mechanisms. Rather than existing as independent units, Nav channels are part of a signaling complex that involves auxiliary proteins and membrane lipids. My goal is to address fundamental questions on the identities of the Nav channel signaling complex components and to resolve their mechanisms of action at the molecular level. In particular, I will examine to what extent and by what mechanism auxiliary 3-subunits shape Nav channel gating behavior and pharmacology. Furthermore, I intend to investigate how the surrounding membrane lipids influence Nav channel function and their interaction with (3-subunits. Successful completion of my aims will reveal key elements in the Nav channel signaling complex, help define Nav channel function in normal and pathological states, and may offer novel strategies for developing therapeutic drugs.
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0.958 |
2015 — 2018 |
Bosmans, Frank Gert Werner |
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. |
Voltage-Gated Sodium Channel Modulation by Beta1 and Beta4 @ Johns Hopkins University
? DESCRIPTION (provided by applicant) Voltage-activated sodium (Nav) channels form the cornerstones of fast electrical signaling in the human body. On a molecular level, Nav channels consist of four similar domains that each contains a voltage sensor which largely resides within the lipid membrane. These sensors can interact with ?1 and ?4, two associated glycoproteins that regulate the gating properties of the channel and modulate channel expression levels. Although a link between Nav channel mutations and particular diseases has been established, little is known about the regulatory influence of ?1 and ?4 on Nav channels and how mutations within these two molecules relate to epilepsy (?1) and cardiac (?4) syndromes. To begin to understand this causal relationship, we need to establish an interaction model that reflects the mechanism by which ?1 and ?4 regulate the functional properties of the channel. We propose that these ?-subunits tune the response of Nav channels to membrane potential changes by influencing voltage-sensing domains. To help examine this notion, we will assess the impact of an epilepsy-related ?- subunit mutation on its ability to alter correct signaling complex assembly or modify channel gating. To achieve our goals, we will use Nav1.2 as a model channel since this particular isoform can interact with ?1 and ?4 and is a risk gene for epilepsy. Although ?-subunit crystal structures provide atomic resolution information, a relative orientation in respect to the Nav channel is required to understand their interaction. Identification of anchoring residues in both partners will help orient functional regions within the extracellular and transmembrane domains, thereby providing the experimental basis for docking ?1 and ?4 onto the Nav channel. The resulting model will offer a starting point to explain mutational effects, which is necessary to accurately interpret and correct pathogenic behavior.
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0.958 |
2016 — 2019 |
Bosmans, Frank Gert Werner Mankowski, Joseph L [⬀] Ringkamp, Matthias (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. |
Siv-Induced Inflammation Causes Functional Impairment of the Pns @ Johns Hopkins University
? DESCRIPTION (provided by applicant): HIV-induced sensory neuropathy (HIV-SN) is a major global health problem as 35 million people are infected with HIV and a considerable percentage of these will develop neuropathy. HIV-SN poses a major burden on the quality of life of affected patients as many suffer from neuropathic pain that is resistant to antiretroviral therapy as well a other drugs commonly used to treat neuropathic pain. Despite the pressing need for novel therapeutics, the development of new treatment strategies has been hampered by our lack of understanding of the mechanisms underlying HIV-induced neuropathy. Using an SIV/macaque model of HIV-neuropathy that closely recapitulates HIV-induced damage, we propose to investigate the underlying cause of HIV-SN by 1) developing tools that allow the use of corneal confocal microscopy to non-invasively track the development of peripheral neuropathy and 2) measuring levels of SIV-induced inflammatory mediators in plasma and dorsal root ganglia. In this macaque model, we will also record neuronal activity from unmyelinated nociceptive afferents in peripheral nerves to investigate whether such afferents develop signs of peripheral sensitization after infection as sensitization could contribute to spontaneous pain and hyperalgesia seen in patients with HIV-SN. In addition to peripheral nociceptive nerve fibers, nociceptive neurons in DRG may be damaged by inflammatory mediators produced locally in DRG or present in the circulation. Using the patch-clamp electrophysiology technique, we will investigate whether nociceptive DRG neurons develop hyperexcitability during SIV infection and whether inflammatory mediator-sensitive voltage-gated sodium channel isoforms play a role. By correlating the findings obtained with the different techniques, we will obtain a better understanding of the mechanisms underlying HIV-sensory neuropathy to develop new strategies for treatment.
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0.958 |
2019 |
Bosmans, Frank Gert Werner |
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. |
Voltage-Gated Sodium Channel Modulation by Beta1 and Beta4 (R01ns091352)
? DESCRIPTION (provided by applicant) Voltage-activated sodium (Nav) channels form the cornerstones of fast electrical signaling in the human body. On a molecular level, Nav channels consist of four similar domains that each contains a voltage sensor which largely resides within the lipid membrane. These sensors can interact with ?1 and ?4, two associated glycoproteins that regulate the gating properties of the channel and modulate channel expression levels. Although a link between Nav channel mutations and particular diseases has been established, little is known about the regulatory influence of ?1 and ?4 on Nav channels and how mutations within these two molecules relate to epilepsy (?1) and cardiac (?4) syndromes. To begin to understand this causal relationship, we need to establish an interaction model that reflects the mechanism by which ?1 and ?4 regulate the functional properties of the channel. We propose that these ?-subunits tune the response of Nav channels to membrane potential changes by influencing voltage-sensing domains. To help examine this notion, we will assess the impact of an epilepsy-related ?- subunit mutation on its ability to alter correct signaling complex assembly or modify channel gating. To achieve our goals, we will use Nav1.2 as a model channel since this particular isoform can interact with ?1 and ?4 and is a risk gene for epilepsy. Although ?-subunit crystal structures provide atomic resolution information, a relative orientation in respect to the Nav channel is required to understand their interaction. Identification of anchoring residues in both partners will help orient functional regions within the extracellular and transmembrane domains, thereby providing the experimental basis for docking ?1 and ?4 onto the Nav channel. The resulting model will offer a starting point to explain mutational effects, which is necessary to accurately interpret and correct pathogenic behavior.
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0.923 |