Area:
Drug Discovery for Neurodegeneration
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High-probability grants
According to our matching algorithm, Isaac Thomas Schiefer is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2018 — 2021 |
Schiefer, Isaac Thomas [⬀] |
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. |
Development of Attenuated Furoxans as Novel Therapies For Alzheimer's Disease @ University of Toledo Health Sci Campus
Project Summary/Abstract Significant effort has been put toward developing therapies targeted at amyloid-? peptide (A?), the hallmark toxic aggregatory protein associated with AD. Unfortunately, A? targeted therapies have resulted in several costly Phase III clinical failures. This research focuses on developing novel cognition enhancing agents which do not directly target A? but may reverse the effects of A? on cognitive function and provide neurorestorative effects by up-regulating neurogenic gene products. Nitric oxide (NO) mimetics activate an intracellular 2nd messenger known as soluble guanylyl cyclase (sGC) leading to increased cyclic GMP (cGMP) production and increased phosphorylation/activation of cAMP response element binding protein- CREB (pCREB). CREB phosphorylation is recognized as being a crucial regulator of synaptic plasticity, resulting in the production of pro-growth gene products, such as brain derived neurotrophic factor (BDNF), and enhanced synaptic transmission. NO/cGMP/CREB signaling is disrupted in AD via A?-mediated inhibition of NO-induced CREB phosphorylation and synaptic plasticity. Reversal of A? induced memory impairment via agents which activate NO/cGMP signaling results in improved cognitive function. Hence, NO/cGMP activating agents show potential for the treatment of AD. Furoxans are a class of thiol-dependent NO mimetics which may hold potential as novel neurorestorative therapies. Furoxans are distinct because they exhibit `tunable' NO mimetic effects. A unique molecular structure distinguishes furoxans from classical NO mimetic nitrates and makes it possible to engineer molecules with significantly reduced rates of NO mimetic activity. HPLC-MS/MS analysis reveals that furoxan reactivity can be manipulated in a predictable manner to avoid the adverse systemic hypotensive side-effects associated with transient fluxes of NO. Preliminary studies indicate furoxans have good brain penetration, neuroprotective activity, and cognition enhancing effects via NO/cGMP/CREB signaling. This project represents a hit-to-lead optimization campaign for the development of furoxans as novel agents for AD. Our approach includes- 1) synthesis of novel analogs and preliminary screening in PC12 cells for protection against oxidative stress; 2) Counter screening active analogs in a focused in vitro pharmacokinetic battery; 3) validating efficacy to improve synaptic function (ex vivo LTP experiments) and protect primary cortical neurons from A? induced toxicity; 4) a focused PK/PD study to define a relationship between orally administered furoxan, unbound furoxan in the hippocampus, and engagement of NO/cGMP signaling. A brief dose escalation study will confirm that furoxans do not affect systemic blood pressure or possess acute toxicity prior to conducting a pilot in vivo efficacy in 3xTg transgenic AD mice. Primary outcomes focus on the ability to improve spatial working and contextual fear memory in 3xTg mice.
|
1.009 |
2018 — 2019 |
Schiefer, Isaac Thomas [⬀] |
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. |
In Vivo Photoaffinity Labeling Using Casper Zebrafish For Target Identification @ University of Toledo Health Sci Campus
PROJECT SUMMARY. Modern synthetic organic chemistry methodologies and internet `how-to' websites have likely made it impossible to prevent the presence of synthetic psychoactive agents in our society. Determining the mechanism of action (MOA) of central nervous system (CNS) drugs is a cumbersome task but is essential to better treat substance abuse and episodic toxicity. On a fundamental level, psychoactive drugs must bind to biological targets to elicit an effect. This work aims to develop a platform with the ultimate goal of studying ligand-receptor interactions in live animals to unravel the MOA of modern psychoactive agents. Photoaffinity labeling (PAL) has been used to successfully map ligand binding domains for several receptor and drug classes because PAL probes covalently attach to all binding partners upon transient radiation with UV light. However, the use of PAL has been restricted to cell culture or tissue homogenates because most animals have endogenous molecules capable of blocking penetration of UV light. Pigment free zebrafish, known as casper fish, have been developed which completely lack pigmentation and may therefore be useful for in vivo PAL studies. The creation of a PAL derivative of a psychoactive agents may allow us to identify binding partners at the same time that drug induced behavioral changes are observed via transient UV radiation and follow-up bioconjugation chemistry to determine protein modification. This small grant has two aims. We will synthesize a well-defined library of PAL probes to examine the structure activity relationship of methamphetamines and MDMA. Probes will utilize an arylazide photoreactive group and a terminal alkyne for conjugation with biochemical reporters- a fluorophore for visualization. Aim 2 will involve PAL method development. This will include defining behavioral dose-response in casper zebrafish (effective dose [ED50]). Once ED50's are defined, PAL will be performed as follows: incubate casper zebrafish with probe (at ED50) ? observe behavioral response ? irradiate with UV light ? dissect out and homogenize brain ? click to fluorophore ? SDS PAGE ? observe protein modification. Follow-up competition experiments and PAL background controls will validate findings. The experimental design above may allow us, for the first time, to observe direct binding partners responsible for behavioral changes associated with psychoactive agents. Upon establishing the feasibility of this approach we will seek to develop a larger probe library based on MDMA, methamphetamines, and novel synthetic cathinones (i.e. bath salts) in an attempt to correlate binding partners with toxicity, hallucinogenic effects, and psychostimulatory activity.
|
1.009 |