2015 — 2016 |
Marr, Robert Anthony Stutzmann, Grace E. [⬀] |
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.) |
Validating Novel Ryanodine Receptor-Targeted Compounds For Ad Therapeutics @ Rosalind Franklin Univ of Medicine & Sci
? DESCRIPTION (provided by applicant): Currently, there are no effective strategies or treatments to preserve cognitive function in AD patients. The recent series of failed clinical trias designed to target A? processing or inflammatory pathways highlight the need to explore alternative pathways. Novel compounds that can effectively preserve cognitive function and prevent disease progression in a manner distinct from previous approaches could provide new therapeutic opportunities. To this end, we developed >100 small molecule compounds designed as allosteric modulators of the ryanodine receptor (RyR), a large conductance calcium channel found on the ER membrane, as candidates for clinical testing in early AD or MCI patients. In both human AD patients and AD mouse models, increased RyR2 expression precedes the amyloid deposition, neuronal loss, and cognitive impairments. In AD mouse models, increased RyR-evoked calcium release is greatest in dendritic spines and synaptic compartments, and contributes synaptic pathology, increased amyloid and tau pathology, disrupted memory function, and other AD-defining features. We and others have recently demonstrated that treating AD mice with dantrolene, a RyR channel stabilizer, resulted in exciting therapeutic effects. Although our treatment regimens differed, the consistent results demonstrate normalized calcium signaling (Chakroborty et al., 2012a; Oules et al., 2012; Stutzmann et al., 2006), normal synaptic transmission and plasticity expression (Chakroborty et al., 2012a), restored synaptic integrity (Stutzmann lab), reduced A levels (Chakroborty et al., 2012a; Oules et al., 2012; Peng et al., 2012), restored RyR isoform levels (Chakroborty et al., 2012a; Oules et al., 2012), and improved performance on memory tests (Oule et al., 2012; Peng et al., 2012). These data support a strong case for stabilizing RyR function, with a focus on RyR2, as a therapeutic strategy. The objective of this study is to test and optimize compounds that will function as RyR channel regulators, serving to suppress excessive calcium release while maintaining physiological functions. The central hypothesis is that stabilizing RyR-mediated calcium release with novel small molecule compounds will normalize calcium signaling, preserve synaptic function, and reduce histopathology, thus serving as an effective therapeutic strategy to prevent cognitive decline in AD. This will be accomplished with the following Aims: 1. Identify optimal RyR2 stabilizing compounds in model cells and iPSC from human AD patients using calcium imaging, electrophysiological and immunoassay techniques. 2. Demonstrate broad efficacy of successful novel compounds on calcium signaling, synaptic plasticity and histopathology in chronically treated 3xTg-AD mouse models. The significance to public health is the development of an effective and novel treatment for AD.
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0.981 |
2016 — 2017 |
Marr, Robert Anthony |
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.) |
Nep-Like Endopeptidases in Traumatic Brain Injury and the Associated Dementias @ Rosalind Franklin Univ of Medicine & Sci
? DESCRIPTION (provided by applicant): The recognized incidence and pathological impact of traumatic brain injury (TBI) has increased tremendously in recent year. In particular the causal links between TBI and chronic traumatic encephalopathy (CTE) are becoming better understood. Many of the pathological hallmarks of Alzheimer's disease (AD) are shared with early changes in TBI and with the pathology of CTE. Of note are the rapid elevations of the amyloid-beta (A?) peptide after TBI and the accumulation of A? in relation to CTE. Considering the importance of A? to AD, it is reasonable to implicate this peptide in the response to TBI and the development of CTE. Natural mechanisms of clearance of A? are important in the progression of AD and so these clearance mechanisms may also be important in TBI/CTE. Of note are the A?-degrading enzymes neprilysin (NEP) and its homolog neprilysin-2 (NEP2) which are important for controlling cerebral A? levels. Therefore, we propose a role for these enzymes in TBI/CTE. The central hypothesis is that NEP or NEP2 expression is important for effective recovery after TBI and protects from the development of CTE. In Aim 1, we will test this hypothesis through the use of NEP and NEP2 knockout as well as NEP transgenic mice which will receive mild-repetitive or single severe TBI, after which they will be assessed for neurological function and pathology acutely after injury. We predict that the lack of NEP or NEP2 will exacerbate aspects of acute pathology after injury while NEP overproduction will ameliorate pathology. In Aim 2 we will test for the effects of NEP or NEP2 alterations on chronic development of CTE-like pathology months after injury involving multiple mild or single severe TBI. In this aim we expect that decreased NEP or NEP2 will exacerbate, while increased NEP will protect against aspects of CTE-like pathology (learning and memory deficits, anxiety) in our models. This work is innovative because the effects of reduced or enhanced NEP-like expression on the progression of TBI and CTE have not been addressed. Also, the role of the NEP/NEP2 substrate, A?, in TBI and CTE is also not yet fully understood, and this project will investigate an alternate means of manipulating A? levels without altering APP and BACE1 or using secretase inhibitors. These experiments will shed light on the role of these A?-degrading endopeptidases in TBI and CTE allowing for the potential development of therapies based on augmenting their activity post injury. Furthermore, this work could help in identifying gene expression markers that predict outcome after TBI.
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0.981 |