Research Development: Bedside to Bench and Back
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1 Research Development: Bedside to Bench and Back Matt Bellizzi, MD PhD Department of Neurology University of Rochester School of Medicine and Dentistry Rochester, NY "I can walk down the hall just fine, but I'd trade that for a wheelchair if I could have my mind back" 2
2 Treating cognitive impairment in MS: from clinical problem to research question to treatment Pathophysiology Disease models Identifying therapeutic targets Screening candidate treatments Preclinical testing Safety, efficacy Investigational New Drug application Clinical trials Early phase, late phase Clinical practice Treating cognitive impairment in MS: from clinical problem to research question to treatment Pathophysiology Disease models Identifying therapeutic targets Screening candidate treatments Preclinical testing Phase 1: safety, dosing Safety, efficacy Phase 2: efficacy Investigational New Drug application Phase 3: effectiveness Phase 4: post-marketing Clinical trials Early phase, late phase Clinical practice
3 Treating cognitive impairment in MS: from clinical problem to research question to treatment Pathophysiology Disease models Identifying therapeutic targets Screening candidate treatments Preclinical testing Safety, efficacy Investigational New Drug application Clinical trials Early phase, late phase Clinical practice Pathological basis for cognitive impairment in MS? Lesion effect - amnesia in a patient with hippocampal demyelination Cognitive impairment in a patient with minimal lesion burden
4 Cognitive impairment in MS correlates with gray matter injury Control MS x 5 yrs MS x 5 yrs cognitively impaired Calabrese, Neurology 74:321 (2010) MS gray matter pathology - hippocampus Control MS Microglial activation Demyelination Loss of synapses Dutta, Ann Neurol 69:445 (2011)
5 Neuronal injury associated with activated microglia in MS cortex Meningeal inflammation Microglial activation C O R T E X Neuronal Injury Magliozzi, Ann Neurol 68: 477 (2010) Cortical Layer Do activated microglia trigger neuronal injury in MS gray matter?
6 EAE hippocampus: a mouse model of MS gray matter degeneration Control EAE 25 day 55 day Synapses (PSD95) 10 µm p * Sham EAE 25 d * Sham EAE 55 d EAE hippocampus: a mouse model of MS gray matter degeneration Control EAE 5 µm Microglia / Synapses (Iba1) (PSD95)
7 Attenuation of microglial activation protects against hippocampal synapse loss in EAE mice Control EAE EAE-URMC099 Microglia (Iba1) Synapses (Synapsin1) Myelin (MBP) Identifying targets for neuroprotection: an in vitro model of microglial activation and neuronal injury
8 Synaptic injury in neuron-microglia co-cultures BV-2 microglia cell line LPS Cultured hippocampal neurons GFP BV-2 hippocampal co-culture Activated microglia promote excitotoxic injury
9 Activated microglia promote excitotoxic injury Excitatory activity Activated microglia promote excitotoxic injury
10 Activated microglia promote excitotoxic injury Activated microglia promote excitotoxic injury
11 Activated microglia promote excitotoxic injury Activated microglia promote excitotoxic injury
12 Activated microglia promote excitotoxic injury Activated microglia promote excitotoxic injury
13 Blocking platelet-activating factor (PAF) receptor prevents activity-dependent injury Excess PAF disrupts hippocampal synaptic plasticity Synaptic stimulation LTP
14 Excess PAF disrupts hippocampal synaptic plasticity Treating cognitive impairment in MS: from clinical problem to research question to treatment Pathophysiology Disease models Identifying therapeutic targets Screening candidate treatments Preclinical testing Safety, efficacy Investigational New Drug application Clinical trials Early phase, late phase Clinical practice
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