Area:
Protein Synthesis, Neurological Disease, Neural Circuits
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High-probability grants
According to our matching algorithm, Stephen M. Eacker is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2017 |
Eacker, Stephen Matthew |
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. |
Characterization of a Novel Flpo Recombinase Line Targeting Nigral Dopamine Neurons @ Johns Hopkins University
Project Summary Characterization of a novel Flpo recombinase line targeting nigral dopamine neurons The dopamine (DA) neurons of the substantia nigra pars compacta (SNc) have been extensively studied because of their selective vulnerability to degeneration during Parkinson's disease (PD) progression. The DA neurons of the closely neighboring ventral tegmental area (VTA) are largely spared during PD progression; a phenomenon that remains poorly understood. Studies attempting to separate SNc and VTA function using modern genetic tools have been limited by the lack of recombinase lines that effectively separate these two nuclei. Recent studies have shown that aldehyde dehydrogenase 1a1 (Aldh1a1) is expressed selectively in SNc DA neurons and this subpopulation of DA neurons undergoes the most extensive degeneration in sporadic PD. Also it has been recently shown that Aldh1a1 is capable of participating in GABA synthesis in a pathway independent of the classic GABA biosynthetic pathway. Thus Aldh1a1+ DA neurons represent an anatomically and neurochemically distinct population of DA neurons relevant to PD. To gain genetic access to this population we have developed a Flpo recombinase knock-in line at the mouse Aldh1a1 locus. Using this novel Aldh1a12A-Flpo line in an intersectional approach with the dopamine transporter Cre line (Slc6a3IRES-Cre) we will be able to gain genetic access to both Aldh1a1+ and Aldh1a1- DA neurons. This proposal is designed to test the feasibility of using Aldh1a12A-Flpo to selectively target SNc DA neurons and to determine their target fields and diversity of molecular phenotypes. We also evaluate the utility of intersectional approaches to specify VTA DA neurons using Aldh1a12A-Flpo with Slc6a3IRES-Cre transgenic mice.
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1 |
2018 |
Dawson, Ted M. [⬀] Eacker, Stephen Matthew |
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. |
Dynamics of Synaptic Connectivity in a Mouse Model of Alpha-Synuclein Transmission @ Johns Hopkins University
The synucleinopathies are collection of disorders characterized by accumulation of aggregated ?-synuclein and include dementia with Lewy bodies (DLB), Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and multisystem atrophy (MSA). These synucleinopathies show different distributions of ?-synuclein pathology but all show pathology in the substantia nigra dopamine neurons. Together, DLB and PDD are estimated to make up ~25% of all degenerative dementias worldwide. Based on post-mortem brain studies, Heiko Braak and colleagues hypothesized that ?-synuclein pathology spreads from cell to cell in a retrograde (dendrite to axon) pattern from the brain stem anteriorly. Subsequent studies have observed ?-synuclein aggregates in PDD and DLB gastrointestinal (GI) tract. Coupled with observations that vagotomy is significantly protective against PD suggests that the origin of ?-synuclein spreading pathology may be in the GI tract. We have modeled this process using injection of ?-synuclein pre-formed fibrils (PFFs) into the pylorus and duodenum of mice. We observe a spread of ?-synuclein pathology in a pattern reminiscent of that described by Braak. Using this model, we propose a series of studies to identify neural circuits that accumulate ?-synuclein aggregates in GI-inject PFF mice and determine how this accumulation affect the synaptic function and connectivity within the circuit. In this application, we propose to (1) molecularly and anatomically identify input neurons to subtantia nigra dopamine neuron using recombinant rabies virus based RNAseq method, (2) determine the timecourse and extent of toxic ?-synuclein spread in these input neurons, and (3) determine the consequence of ?-synuclein spread on the function and connectivity of neurons innervating the nigral dopamine neurons. At the completion of these experiments, we will have improved our understanding how ?-synuclein disrupts neural circuits involved in cognitive processes, the underlying cause of dementia in DLB and PDD.
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