2010 — 2014 |
Todd, Peter K |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Pathogenic Mechanisms in Fragile X Tremor Ataxia Syndrome
DESCRIPTION (provided by applicant): Fragile X Tremor Ataxia Syndrome (FXTAS) is a common erited cause of gait disorder and tremor affecting upwards of 1:800 males. FXTAS is caused by an expanded "CGG" nucleotide repeat in the 5'untranslated region of the Fragile X Mental Retardation gene, FMR1. In patients and animal models, this expanded CGG repeat is associated with elevated FMR1 mRNA expression, neurodegeneration, and ubiquitin- positive intranuclear neuronal inclusions that contain the expanded CGG repeat mRNA and several proteins. Work to date has focused on the potential role of the CGG repeat in eliciting neurodegeneration via an RNA gain-of-function mechanism. However, critical aspects of disease pathology are not easily explained by a pure mRNA mediated sequestration process. Our central hypothesis is that the CGG repeat expansion contributes to neuronal degeneration in FXTAS via multiple, overlapping molecular mechanisms. These mechanisms include transcriptional dysregulation of the FMR1 gene in cis and RNA mediated gain of function toxicity leading to anomalous RNA splicing events and alterations in protein quality control pathways. Our proposal to test this hypothesis is divided into three aims. Aim 1 will examine the mechanisms by which FMR1 mRNA transcription is increased, focusing on the histone acetylation status at the FMR1 locus. Aim 2 will examine the role of the ubiquitin proteasome system in FXTAS pathogenesis. Both aims one and two will utilize a drosophila model of FXTAS as well as patient derived lymphoblasts. Aim 3 will employ inducible pluripotent stem cells from FXTAS patient fibroblasts that are differentiated into neurons. We will determine the alternative transcriptome profile of these human FXTAS neurons to address the hypothesis that sequestration of RNA binding proteins in FXTAS leads to aberrant mRNA splicing. Taken together, these studies should significantly extend our understanding of this neurodegenerative disorder and assist in identification appropriate candidate therapeutic targets. PUBLIC HEALTH RELEVANCE: Fragile X Tremor Ataxia syndrome (FXTAS) is a common inherited rodegenerative disorder that causes difficulties with walking, shaking of the limbs and dementia in older men. Our work proposes to test the idea that the genetic cause of FXTAS leads to neuronal death by two overlapping mechanisms: it increases the transcription of the mutant gene into RNA and it makes that RNA toxic to neurons, such that problems develop with the way these cells process and degrade other RNAs and proteins. To test our hypothesis we will utilize a fruit fly model of the disorder and we will also derive inducible pluripotent stem cells from patients with the disease so that we can study human derived neurons with the causative mutation. Taken together, we feel these studies will tell us a lot about what causes FXTAS and what we need to do to develop treatments for it.
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0.958 |
2010 — 2011 |
Smith, Eliot (co-PI) [⬀] Bollen, Johan [⬀] Todd, Peter (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Rapid: Models of Social Contagion of Charitable Sentiment Towards Haiti On Twitter.
This is a small RAPID award to provide support for a project involving the analysis of the emotional content of large-scale Twitter data to shed light on important and enduring theoretical questions in Social Psychology. The investigators have expertise in Social Informatics and Social Psychology, and together they will collect and analyze a large-scale collection of tweets (short messages broadcast using the Twitter social networking service) that reference the Haiti earthquake disaster. The emotional content of these tweets will be tracked over time in an automated fashion using an expanded version of the Profile of Mood States test previously developed by one of the PIs. The social networks connecting Twitter users will be traced from users' "Friend of" and "Follower" data which will enable the researchers to examine the bi-directional influence of social factors with emotional responses and prosocial behavior. This analysis of Twitter data (both tweet content and social networking data of Follower and Friends networks) will permit an analysis of the impact of emotions on donating or other forms of prosocial behavior, as well as the effect of donating on subsequent emotional states. Using Twitter data to address what represents longstanding theoretical issues in Social Psychology allows the researchers to avoid many of the limitations of laboratory-based studies that include generally short time duration, practical and ethical limitations on the use of high impact manipulations, and often a reliance on college undergraduates as participants.
The broader impacts of this work are two-fold. First, the proposed program of research will promote teaching, training, and learning, by training and mentoring undergraduate research assistants and graduate students. Second, the proposed research will address questions that can be applied more broadly, to understand why and how people donate or perform other prosocial behaviors, and to encourage them to do so more frequently. Knowing what emotional states tend to lead to donation, and how people respond to information about their friends or acquaintances donations will allow charitable organizations to construct more effective appeals.
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0.957 |
2014 — 2021 |
Todd, Peter K |
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. |
Cgg Repeat Associated Translation in Fragile X-Associated Tremor/Ataxia Syndrome @ University of Michigan At Ann Arbor
Fragile X-associated tremor/Ataxia syndrome (FXTAS) is one of a large class of human neurological disorders that result from instability and expansion of nucleotide repeats. In FXTAS, a CGG nucleotide repeat expands in the 5? untranslated region of the fragile X gene, FMR1, and triggers formation of aggregated protein inclusions in the patient brains. Our group found that the FXTAS CGG repeat gets translated into toxic homopolymeric proteins despite its location outside of a canonical open reading frame through a process known as repeat associated Non-AUG initiated (RAN) translation. RAN translated proteins accumulate in patient tissues and contribute to CGG repeat associated toxicity in multiple model systems. In this proposal, we will explore how this alternative translational initiation occurs mechanistically. Our preliminary data suggests that RAN translation at CGG repeats is selectively enhanced by cellular stress, which typically blocks protein synthesis. In parallel, CGG repeats directly elicit cellular stress and trigger stress granule formation. Our central hypothesis is that CGG RAN translation and cellular stress participate in a feed-forward loop that drives neurodegeneration. Our collaborative team will directly test this hypothesis by using biochemical techniques as well as drosophila, mouse and human induced pluripotent stem cell models of FXTAS. In Aim 1 we will determine how cellular stress selectively activates RAN translation, focusing specifically on initiation factors that underlie this process. In Aim 2, we will elucidate how CGG repeats elicit cellular stress and influence stress granule dynamics and whether interventions in this process impact repeat toxicity. In Aim 3, we will test whether selective blockade of cellular stress pathways can disrupt this feed forward loop and alleviate CGG repeat associated toxicity across disease models. Together, these studies will illuminate critical events in the pathogenesis of FXTAS and other nucleotide repeat expansion disorders while rigorously testing two complementary & innovative approaches to selective RAN translation blockade.
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0.958 |
2014 |
Todd, Peter K |
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. |
Cgg Repeat Associated Translation in Fragile X-Associated Tremor/Ataxia Syndrome-Diversity Supplement
Title: CGG repeat associated translation in Fragile X-associated Tremor/Ataxia Syndrome. Abstract: Dominantly inherited nucleotide repeat expansion disorders are thought to elicit neurodegeneration in one of two ways: 1) The repeat as RNA can bind to and sequester specific proteins, preventing them from performing their normal functions; or 2) If the repeat is translated into protein, the repetitive amino acid expansion can trigger toxicity through a variety of mechanisms including protein misfolding and aggregation. Traditionally, the dominant contribution of each pathogenic mechanism has been suggested by the repeat's location within the disease gene, with exonic repeats exerting toxicity primarily as protein and non-exonic repeats presumably acting via RNA-mediated mechanisms. Recent data, however, indicate that repeats in non-coding regions of transcripts can be aberrantly translated into proteins through Repeat Associated Non- AUG initiated (RAN) translation. In light of this new finding, defining the relative contributions of RNA- and protein-mediated toxic processes in each repeat expansion disorder has surfaced as a critical issue in the field. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an inherited neurodegenerative disorder that results from a CGG repeat expansion at the beginning of the fragile X gene, FMR1. It is characterized pathologically by the formation of proteinaceous inclusions in the brains of patients. Work to date suggests that the repeat is toxic as RNA, but our group recently showed that the CGG repeat expansion also elicits RAN translation (CGG RAN translation) to produce an aggregation-prone, homopolymeric polyglycine containing protein. This protein aggregates in model systems and is present in inclusions in FXTAS disease brain. In this proposal, we will determine whether the CGG repeat in FXTAS triggers neurodegeneration as RNA, as a toxic protein, or both, and then interrogate how this newly discovered RAN translation occurs mechanistically. To address these questions, we will utilize new fly models of FXTAS to determine the relative abilities of CGG repeats as RNA and as RAN translated proteins to elicit neurodegeneration. We will then extend these findings to pathological and behavioral assessments of two knock-in mouse models of FXTAS that differ in their ability to support CGG RAN translation. In parallel, we will employ a series of biochemical and cell-based approaches to explore the mechanisms underlying CGG RAN translation. These studies should provide critical insight into FXTAS pathogenesis while offering a relevant case-study for other repeat expansion disorders, and in the process facilitate the identification of proximal therapeutic targets based on improved understanding of disease mechanisms.
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0.958 |
2016 — 2020 |
Todd, Peter K |
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. |
Hexanucleotide Repeat Translation in Als and Frontotemporal Dementia
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) are common neurodegenerative disorders that are progressive, fatal, and without effective treatment. Recently, the most common known cause of ALS and FTD was identified as an intronic GGGGCC hexanucleotide repeat expansion in the gene C9orf72 (C9FTD/ALS). This repeat triggers synthesis of toxic proteins via a process known as Repeat Associated Non-AUG (RAN) Translation. These RAN peptides kill neurons and are sufficient to cause neurodegeneration in model systems. We know very little about how RAN translation at C9 repeats (C9 RANT) actually occurs. The objective of this proposal is to determine the mechanisms underlying C9 RAN and to identify methods of blocking it as a first step towards novel therapeutic development. Our central hypothesis is that C9 RAN utilizes a non-canonical translational initiation pathway that can be selectively blocked. Moreover, we predict that preventing C9 RAN will stop neurodegeneration elicited by GGGGCC repeats. To test these hypotheses, we developed robust and quantitative in vitro and cell based assays of C9 RANT, as well as a collection of models derived from patient induced pluripotent stem cells, rodent neurons, and Drosophila. Using these tools, we will define the mRNA species that undergo C9 RANT, identify the critical RNA and protein based factors that allow for C9 RANT and test whether suppressing C9 RANT by modulating the surrounding sequence or protein factors can block toxicity in model systems. Together, these studies should provide us with a working map of how C9 RAN occurs and what steps can be taken to prevent it. This project has broad reaching implications both for our understanding of how RAN translation contributes to disease as well as providing a logical path towards therapeutic development in C9FTD/ALS and other neurodegenerative nucleotide repeat disorders.
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0.958 |