1996 — 1998 |
Hutton, Michael L. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Molecular Biology @ Mayo Clinic Coll of Med, Jacksonville
molecular biology; genes; Alzheimer's disease; biomedical facility; molecular cloning;
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0.958 |
1998 — 2000 |
Hutton, Michael L. |
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. |
Identification of the Gene For Ftdp On Chromosome 17 @ Mayo Clinic Coll of Med, Jacksonville
DESCRIPTION: A number of families (13) with fronto-temporal dementia and parkinsonism (FTDP) have been linked to the same (approx. 2 cM) region of chromosome 17q21. The clinical features of this disease include early behavioral change and motor manifestations leading to progressive memory loss and dementia. At autopsy, the patients with FTDP-17 all show fronto-temporal atrophy with neuronal cell loss, neruopil vacuolation and gliosis in both white and gray matter. Argyrophilic and/or tau positive neuronal inclusion are observed in some families. Ballooned neurons are found in all cases that have been examined to date. The overall of this study is to identify the gene for and the pathogenic mutations which cause FTDP-17. In order to perform this task the candidate region for FTDP-17 will be minimized using data from a series of FTDP-17 kindreds and the candidate region will be physically mapped in YACs and PACs. Known genes and ESTs will be mapped into the FTDP-17 region and then prioritized for study as candidates for FTDP-17. Sequence analysis of candidate genes (novel and previously identified, ie GFAP and tau) will be performed to identify mutations. Once the FTDP-17 gene has been identified the prevalence of the disease will be studied in both a prospective community-based dementia cohort in Rochester, Minnesota and in two autopsy cohorts.
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0.958 |
1999 — 2002 |
Hutton, Michael L. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Analysis of the Role of 3 and 4 Repeat Tau in Vitro and in Vivo @ Mayo Clinic Coll of Med, Jacksonville
The recent identification by our group of mutations in the 5' splice site of tau exon 10 that are associated with Fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) demonstrated for the first time that the ratio of Tau containing 4 and 3 microtubule binding repeat is crucial to the correct functioning of Tau in the adult Human brain. The splice site mutations (+3, +13, +14 and +16) all destabilize a stem-loop structure that is likely involved in regulation of exon 1- alternative splicing by inhibiting U1 snRNP binding and exon definition. The mutations are thought to cause increased U1 snRNP binding, through disruption of the stem-loop, which directly leads to increased splicing of exon 10 and increased 4 repeat Tau. We were the first to demonstrate that the mutations increasing splicing of exon 10 and increased 4 repeat Tau. We were the first demonstrate that the mutations increased splicing of tau exon 10 by RT-PCR analysis of FTDP-17 brains and also through the use of an in vitro splicing assay. Further we have since demonstrated, using the in vitro splicing assay, that it is indeed the stem-loop structure in the 5' splice site of exon 10 that is disrupted by the FTDP-17 mutations that which plays a major role in the regulation of alternative splicing of this exon. The fact that mutations that increase the proportion of 4 repeat Tau by as little as two fold are pathogenic in FTDP-17 indicates the importance of the ratio of Tau isoforms with 3 and 4 repeats to the correct functioning of Tau. In other species the ratio of 4 repeat to 3 repeat Tau can vary widely and in addition it has been known for some time that in fetal brain only 3 repeat Tau is observed with the generation of 4 repeat isoforms not occurring until some time after birth. Thus the 4 repeat to 3 repeat Tau ratio seems virtually certain to reflect if not to underlie, some fundamental differences in the role of neurons in different species and during development. This project is designed to increase our understanding of the regulation of the ratio of 4 to 3 repeat Tau, why this ratio is important in the correct functioning of neurons and why disruption of this ratio can result in neurodegeneration.
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0.958 |
1999 — 2003 |
Hutton, Michael L. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Tau and Neurodegeneration @ Mayo Clinic Coll of Med, Jacksonville
In this proposal we describe projects that aim to determine the mechanism by which mutations in the tau gene cause the neurodegeneration associated with Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). In addition we aim to examine the role of Tau in neurodegeneration in other diseases including Progressive supranuclear Palsy (PSP), Alzheimer's Disease, Pick's Disease and Cortico-basal degeneration (CBD). The PI's team reported the identification of missence and splice site mutations in tau, associated with FTDP-17 in the journal "Nature" in June of this year. The Projects are as follows: The Genetics of FTD and Tauopathies. This project will use genetic analysis to examine the possible association of variation in the tau gene with PSP, Pick's disease and CBD. In addition this project aims to identify the gene on chromosome 3 that is also linked with FTD. Mutations at this locus generate a phenotype that is almost indistinguishable from FTD-17 and thus it is important to identify this gene and determine its relationship, if any, with tau. Pathobiology of neurodegenerative disorders linked to mutations in the tau gene. The location of the missence mutations in the tau gene suggests that these likely affect the ability of Tau to bind microtubules. This project will examine this hypothesis using in vitro tubulin binding assays and will also study the effect of the mutations on the polymerization of Tau into fibrils. In addition this project will examine the effect of mutant Tau in transfected cells and will analyze the Tau from the brains of transgenic mice generated in projects 3 and 4. Analysis of the Role of 3 and 4 Repeat Tau in vitro and in vivo. This project will initially utilize in vitro splicing assays to determine the regulation of exon10 alternative splicing that is disrupted by the FTDP-17 splice site mutations. Subsequent studies that will performed in vitro, in transfected cells, and in vivo, in gene targeted mice, will examine the differing roles of 4 repeat and 3 repeat Tau in neuronal function. In addition the gene targeted tau mice will be used to test the hypothesis that the ratio of Tau4 and 3 repeat isoforms influences the toxicity of Abeta in vivo. Transgenic Modeling of Tauopathy. This project will utilize transgenic animals to model the effect of the Tau missence mutations in vivo. The brains of animals expressing wild type and mutant Tau cDNA constructs will be examined will be examined for the neurofibrillary tangles and neurodegeneration that are associated with FTDP-17. In addition animals expressing Human genomic tau constructs will be studied to see the effect of expressing Human Tau isoforms on Abeta sensitivity. These projects will operate around a Neuropathology Core whose broad goal will be to provide detailed morphological characterization of brains from Human patients and animal models that are derived from the research projects.
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0.958 |
2002 — 2005 |
Hutton, Michael L. |
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. |
Tangle Formation in P301l Transgenic Mice @ Mayo Clinic Jacksonville
DESCRIPTION (provided by applicant): Tau pathology is a key feature in numerous neurodegenerative disease including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia and parkinsonism linked to chromosome 17. The events preceding the development of neurofibrillary and other types of tau pathology including associated neurodegeneration are largely unknown. Because tissues are generally unavailable from early stage patients with tauopathies, we intend to utilize a novel mouse model that we have generated to study the progression of neurofibrillary pathology. These transgenic mice express human tau containing an FTDP-17 mutation, P301L, and develop tau neurofibrillary tangles, neuronal loss, amyotrophy, and behavioral and motor deficits. The neurofibrillary tangles in these mice recapitulate essentially all of the features of these lesions in Human tauopathies, including Alzheimer's disease, and critically are also associated with neuronal loss. In addition, the distribution of the pathology and the psychomotor deficits in the tau mice resemble some aspects of progressive supranuclear palsy, amyotrophic lateral sclerosisparkinsonism-dementia (ALS-PD) and variants of FTDP-17. In this project we will perform a series of studies to determine the molecular mechanisms that underlie pathogenesis in the tau (P301L) transgenic mice. cDNA generated from midbrain, pons and spinal cord regions from the P301 L tau mice will be subjected to microarray analysis to identify and profile genes that have altered expression levels during the onset and progression of tangle pathology. To study the effect of tau phosphorylation on tangle formation, which has been suggested as a major initiating event in the pathogenesis of tauopathies, P301L animals will be crossed with mice over expressing either GSK3beta or p25, the constitutive activator of cdk5. Both cdk5 and GSK3beta have been proposed as major tau kinases in both normal brain and in the pathogenesis of disease. Finally, to determine if oxidative stress is associated with the pathology seen in the P301L mice, we will look at markers for oxidative damage of DNA, lipid, and protein. The information from this study will provide a greater understanding of the development of neurofibrillary pathology and associated neurodegeneration in tauopathies as well as the factors that can modify the onset and progression of the pathology.
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0.958 |
2003 — 2006 |
Hutton, Michael L. |
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. |
Amyloid and Tau Pathology in a Transgenic Model @ Mayo Clinic Jacksonville
DESCRIPTION (provided by applicant): We recently developed a transgenic mouse model of neurofibrillary tangle formation by expressing mutant tau (P301L). When this mouse model is crossed with mutant APP transgenic mice (Tg2576), the double transgenic progeny (TAPP) develop amyloid plaques and enhanced limbic NFT pathology. This is the only published mouse model to date that develops both amyloid plaques and tangles. More importantly the TAPP mice provide evidence that APP/Abeta interacts with tau to cause enhanced NFT pathology in vulnerable regions in these mice. In this proposal we aim to investigate the nature of this interaction and also to generate an improved tau/APP mouse model by crossing the tau(P301L) mice to TgCRND8 APP mice. The application has four Specific Aims: In Aim 1, we will investigate the accumulation of hyperphosphorylated tau in the TAPP mice to determine if activation of specific kinases might explain the enhanced limbic NFT pathology in these mice. In Aim 2, Ap vaccination will be used as a tool to prevent amyloid deposition in the TAPP mice to determine if AI3 clearance will also block cortico-limbic NFT formation. In Aim 3, we plan to replicate and extend our findings in the TAPP mice by crossing the tau(P301L) mice to a second mutant APP mouse, TgCRND8 (generated by Dr Westaway). The TgCRND8 mice develop amyloid deposition by 3 months of age and thus this tau/APP mouse model will determine if accelerated amyloid deposition will also cause accelerated and more extensive formation of cortico-limbic NFT pathology. Last in Aim 4, the tau(P301L)/TgCRND8 mice will be immunized with Abeta to determine if prevention and clearance of amyloid pathology will block NFT formation and improve cognitive function in mice with plaques and tangles.
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0.958 |
2004 — 2006 |
Hutton, Michael L. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Genetics of Ftd and Motor Neuron Disease
Fronto-temporal dementia (FTD) is a heterogeneous condition characterized by early behavioral change, cognitive decline and atrophy of the frontal and temporal lobes. The microscopic pathology varies markedly in different forms of the disease with some cases having tau-positive neuronal inclusions. However, the majority of FTD cases (approximately 60%) lack tau-positive lesions displaying mainly a microvacuolization of the superficial neuropil in the cortex. A proportion of these cases (10-15%) however do have ubiquitin-positive inclusions in motor neurons and show evidence of motor neuron degeneration (MND) leading to their designation as FTD-MND cases. Genetic linkage studies in FTD families have revealed three loci on chromosomes 17, 3 and 9. Over 30 mutations in the tau gene account for the majority of autosomal-dominant chromosome 17-1inked cases (FTDP-17). FTDP-17 patients with identified tau mutations develop tau neurofibrillary pathology and many families also develop tau inclusions in glial cells. Recently a locus on chromosome 9q21-22 (chr.9q21-22) was reported by Hosler and colleagues in families with affected members with both FTD and MND. The occurrence of the disease in these families is consistent with an autosomal dominant pattern of inheritance. We have examined our own families with FTD-MND and have also found evidence of linkage to the same locus on chr. 9 in these families. In addition, we have used haplotype analysis in a series of families from Northwest England to suggest a reduced approximate 7 cM critical region on chr9q21-22. The overall aim of this proposal is to identify gene mutations associated with FTD-MND linked to chr.9q21-22 and to study the genotype/phenotype relationship and pathogenic mechanism of mutations in this gene. The identification of this gene will be a crucial step towards understanding the etiology of FTD as well as determining how this disease relates to MND.
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0.958 |
2005 |
Hutton, Michael L. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Administrative and Statistical Analysis Core @ Mayo Clinic Jacksonville |
0.958 |
2005 — 2009 |
Hutton, Michael L. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Role of the Hsp70/Chip Chaperone System in Tau Biology and Pathogenesis @ Mayo Clinic Jacksonville |
0.958 |
2005 — 2007 |
Hutton, Michael L. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Tau and Neurodegeneration Ii: a Therapeutic Target @ Mayo Clinic Jacksonville
Neurofibrillary inclusions composed of the microtubule associated protein tau (tau) are a hallmark feature ot the pathology in several neurodegenerative diseases including Alzheimer's disease, Progressive supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). A causal link between tau dysfunction and neurodegeneration was demonstrated by the idenification of mutations in tau that give rise to FTDP-17. The overall goal of this current program is to identify modifiers that influence the progression of tau pathology, in human neurodegenerative disease and to build on this information to identify therapeutic targets that will form the basis for eventual patient treatments. This goal follows on naturally from the progress made in the first period of funding in which this Program was highly successful in developing both cell culture and transgenic animal models of tauopathy as well as in characterizing the genetic causes of these diseases. The four projects, alongwith a central Neuropathology core, that make up this program will address this overall goal through different but complementary strategies. Project 1 (Dr Farrer) will utilize a genetic approach to identify tau gene variants that increase the risk for developing 4R tauopathy (PSP and CBD) and will determine the mechanism by which these variants lead to disease. This project will thus define a potential therapeutic target in these diseases. Project 2 (Dr Yen) will utilize a cell culture model of early stage tau filament formation and pathogenesis to study the impact of several factors that have been suggested as causes of tauopathy (eg oxidative stress, proteasome inhibition). This project will identify modifiers of tau pathogenesis in this cell model that can then be studied in our transgenic models. Projects 3 (Hutton) and 4 (Duff) will employ transgenic mouse models of tauopathy developed by the Program over the past 4 years to study potential targets already identified by preliminary studies. Project 3 will study the impact of the chaperone Hsp70 and its co-chaperone CHIP on tau pathogenesis whilst Project 4, will examine the impact of tau phosphorylation on pathology and neurodegeneration.
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0.958 |
2006 |
Hutton, Michael L. |
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. |
The Genetics of Chromosome 17q21-Linked Tau-Negative Ftd @ Mayo Clinic Jacksonville
[unreadable] DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a heterogeneous condition characterized by early behavioral change, cognitive decline and atrophy of the frontal and temporal lobes. The microscopic pathology varies markedly in different forms of the disease with some cases having tau-positive neuronal inclusions. However, the majority of FTD cases (approximately 60%) lack tau-positive lesions displaying mainly a microvacuolization of the superficial neuropil in the cortex. A proportion of these cases (10-15%) however do have ubiquitin-positive inclusions in motor neurons and show evidence of motor neuron degeneration (MND) leading to their designation as FTD-MND cases. Genetic linkage studies in FTD families have revealed three loci on chromosomes 17, 3 and 9. Over 30 mutations in the tau gene account for the majority of autosomal-dominant chromosome 17-linked cases (FTDP-17). FTDP-17 patients with identified tau mutations develop tau neurofibrillary pathology and many families also develop tau inclusions in glial cells. It is becoming increasingly clear that a proportion of chromosome 17q21-linked families lack any apparent mutations in the tau gene and, moreover, do possess the neurofibrillary pathology seen in families with defined tau mutations. Importantly, these chromosome 17q21-linked families exhibit ubiquitin positive neuronal inclusions, and a intranuclear ubiquitin positive inclusions are also seen in certain pedigrees. It is possible that the genetic cause of these families results from an unidentified mutation in the tau gene e.g. deep within an intron or from gross alterations of the tau locus, such as duplication. Alternatively, this disease could be caused by an alternative gene in this region. The overall aim of this proposal is to identify gene mutations associated with tau-negative FTD with neuronal and intranuclear ubiqutin positive inclusion linked to chr17q21 and to study the genotype/phenotype relationship and pathogenic mechanism of mutations in this gene. The identification of this gene will be a crucial step towards understanding the etiology of FTD as well as determining how this disease relates to MND. [unreadable] [unreadable]
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0.958 |
2007 — 2008 |
Hutton, Michael L. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Genetics of Frontotemporal Dementia (Ftd) and Motor Neuron Disease
Fronto-temporal dementia (FTD) is a heterogeneous condition characterized by early behavioral change, cognitive decline and atrophy of the frontal and temporal lobes. The microscopic pathology varies markedly in different forms of the disease with some cases having tau-positive neuronal inclusions. However, the majority of FTD cases (approximately 60%) lack tau-positive lesions displaying mainly a microvacuolization of the superficial neuropil in the cortex. A proportion of these cases (10-15%) however do have ubiquitin-positive inclusions in motor neurons and show evidence of motor neuron degeneration (MND) leading to their designation as FTD-MND cases. Genetic linkage studies in FTD families have revealed three loci on chromosomes 17, 3 and 9. Over 30 mutations in the tau gene account for the majority of autosomal-dominant chromosome 17-1inked cases (FTDP-17). FTDP-17 patients with identified tau mutations develop tau neurofibrillary pathology and many families also develop tau inclusions in glial cells. Recently a locus on chromosome 9q21-22 (chr.9q21-22) was reported by Hosler and colleagues in families with affected members with both FTD and MND. The occurrence of the disease in these families is consistent with an autosomal dominant pattern of inheritance. We have examined our own families with FTD-MND and have also found evidence of linkage to the same locus on chr. 9 in these families. In addition, we have used haplotype analysis in a series of families from Northwest England to suggest a reduced approximate 7 cM critical region on chr9q21-22. The overall aim of this proposal is to identify gene mutations associated with FTD-MND linked to chr.9q21-22 and to study the genotype/phenotype relationship and pathogenic mechanism of mutations in this gene. The identification of this gene will be a crucial step towards understanding the etiology of FTD as well as determining how this disease relates to MND.
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0.958 |