2011 — 2012 |
Hart, Michael P [⬀] |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Defining the Role of Ataxin-2 in Als and Tdp-43 Proteinopathies @ University of Pennsylvania
DESCRIPTION (provided by applicant): Neurodegenerative diseases currently have few treatments and no cures. This stems from the lack of understanding of the causes of neuron death in neurodegeneration. Recent research focusing on the proteins discovered to accumulate in the brains of patients, including TDP-43 in amyotrophic lateral sclerosis (ALS), has taken research towards understanding the mechanisms that underlie disease. Modeling disease using pathogenic disease proteins has proved useful for identifying potential pathways, interactions and mechanisms involved in neurodegeneration. In this proposal I will study TDP-43, a pathological protein involved in ALS and frontotemporal dementia, both devastating neurodegenerative disorders. Through modeling TDP-43 related disease in yeast and flies, we have identified a novel interaction between TDP-43 and Ataxin-2, a protein mutated in another neurodegenerative disease, spinocerebellar ataxia type 2 (SCA2). We identified mutations in Ataxin-2 as a novel genetic risk factor for ALS, potentially the most common discovered to date. The TDP-43/Ataxin-2 interaction sits poised as a potential pathogenic mechanism that could provide not only knowledge of disease processes, but also as a potential therapeutic target. Therefore, I will first define the domains of Ataxin-2 and TDP-43 required for the proteins to interact with each other. Second, I will determine if mutations in Ataxin-2 affect the pathological signature of TDP-43, which includes downstream biochemical alterations of the protein, to learn if these mutations influence known disease processes. This will involve training in neuropathology and biochemical methods used to analyze human tissue. Lastly, I will examine if mutations in Ataxin-2 contribute to other neurodegenerative diseases related to ALS that also show TDP-43 involvement. This aspect of the proposal will require training in human genetics methods and analyses, as well as histopathological techniques. Our discovery of a role for Ataxin- 2 in ALS via an interaction with TDP-43 opens up many new avenues for investigation. These experiments will expand our knowledge of the TDP-43/Ataxin-2 interaction and, more broadly, give insight into the similarities and differences of mechanisms underlying different related neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: My proposed experiments and results will aid in the understanding of how a new genetic risk factor contributes to disease, as well as address potential mechanisms underlying a common pathogenic protein. This will give a greater understanding of neurodegenerative disease processes and provide knowledge about a potential therapeutic target for ALS, and perhaps other related neurodegenerative diseases.
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0.964 |
2013 — 2015 |
Hart, Michael P [⬀] |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Motor Neuron Diversity: Markers, Regulatory Mechanisms, and Functional Relevance. @ Columbia University Health Sciences
DESCRIPTION (provided by applicant): Summary The devastating motor neuron diseases Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy cause differential degeneration of subsets of motor neurons. Humans possess hundreds of subtypes of motor neurons that differ in morphology, functional properties, gene expression patterns, molecular signatures, and connectivity. Little is known about how to identify/define terminal motor neuron subtypes or why some are more susceptible to disease processes than others. The goal of this research proposal is use a unique 'bottom-up' approach in C. elegans to identify defining factors and regulatory mechanisms for generating motor neuron subtypes and to understand the functional importance of motor neuron subtype diversity. This will be achieved by studying one cholinergic motor neuron subtype in the C. elegans ventral nerve cord, the AS motor neurons, and the potential role for unc-55 in specifying AS subtype fate. Using C. elegans and analysis of gene regulation, novel factors that molecularly define subtypes from one another will be identified, and the role for unc-55 in regulating these factors will be determined. Next, a candidate approach and an unbiased forward genetic screen will define the regulation of unc-55 in AS motor neurons, utilizing both manual and automated genetic screening techniques in C. elegans. Lastly, the functional importance of the AS motor neurons will be defined by combining optical ablation, optical neuronal activity monitoring, and optogenetic manipulation of AS motor neurons with advanced worm tracking and imaging in freely behaving worms. This proposal will define the specification and function of AS motor neurons, but also broadly address the mechanisms for generating motor neuron subtypes. Unraveling the molecular mechanisms that identify, regulate, and maintain motor neuron subtypes are particularly relevant to motor neuron degeneration, and may provide novel targets for pathogenesis, disease diagnosis, and therapeutics for motor neuron related diseases.
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0.948 |