2009 — 2012 |
Rademakers, Rosa |
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. |
Progranulin: Mutation and Regulation in Neurodegenerative Disease @ Mayo Clinic Jacksonville
DESCRIPTION (provided by applicant): Frontotemporal lobar degeneration represents 10-20% of all dementias and is clinically important because of its earlier age of onset compared to Alzheimer's disease (AD), and its dramatic impact on core human qualities including personality, insight and verbal communication. We recently found that loss-of- function mutations in the gene encoding the secreted growth factor progranulin (PGRN) are an important cause of the most common pathological subtype of FTLD, characterized by neuronal inclusions composed of ubiquitinated TAR DNA-binding protein 43 (TDP43) (FTLD-U). Our working hypothesis is that mutations in PGRN are a more frequent cause of FTLD then initially anticipated and that subtle deregulation of PGRN expression may increase the susceptibility to develop FTLD and a wider range of neurodegenerative diseases. The identification of TDP43 as the pathological protein, not only in FTLD-U, but also in patients with amyotrophic lateral sclerosis (ALS) and in 20-30% of pathologically confirmed AD patients, supports a unifying disease mechanism underlying these disorders. The specific aims of this project are to: 1. Identify the complete spectrum and frequency of mutations in PGRN. In the largest collection of FTLD patients worldwide, we will perform a standardized in- depth mutation screening of PGRN, supplemented with in-vitro functional analyses to determine the disease significance of novel mutations. 2. Identify regulatory cis-acting variants in PGRN that modify disease risk, penetrance or presentation in TDP43 proteinopathies. We will perform genetic association studies of PGRN in FTLD, ALS and AD case-control populations and assess the effect of common PGRN genetic variability on gene expression. 3. Determine the role of miR-659 expression and genetic variability in the development of FTLD. We recently made significant progress in the understanding of the regulation of PGRN when we identified that its expression can be regulated by a specific micro RNA, miR-659. Moreover, we have generated preliminary data suggesting that the common genetic variant rs5848, located in the 3'UTR of PGRN in a predicted binding-site for miR-659, is a major risk factor for FTLD-U through the augmented suppression of PGRN by miR-659. We will perform genetic and expression analyses to determine if deregulation of miR-659 expression in brain or altered genetic variability in the gene encoding miR-659 may contribute directly to the pathogenesis of FTLD-U The proposed studies are relevant to fully appreciate the contribution of PGRN mutations in FTLD leading to increased diagnostic accuracy and counseling. Unveiling the genetic and molecular pathways regulating PGRN may also reveal novel targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process. PUBLIC HEALTH RELEVANCE: This proposal is designed to define the complete PGRN mutational spectrum in FTLD and to determine whether subtle deregulation of PGRN expression may hold susceptibility to a wider range of neurodegenerative diseases. These studies are relevant to fully appreciate the contribution of PGRN mutations in FTLD leading to increased diagnostic accuracy and counseling. Unveiling the genetic and molecular pathways regulating PGRN may also reveal novel therapeutic targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process.
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1 |
2009 — 2013 |
Rademakers, Rosa |
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. |
The Pgrn/Tdp-43 Axis in Alzheimer?S Disease and Neurodegeneration
We identified loss-of-function mutations in the gene encoding the secreted growth factor progranulin (PGRN) as a major cause of familial frontotemporal lobar degeneration with ubiquitin and TDP-43-positive inclusions (FTLD-U). The exact role of PGRN in neurons has yet to be established, however, the loss of functional PGRN in FTLD-U implicates its essential function in neuronal survival. The identification of TDP-43 as the pathological protein, not only in patients with FTLD-U with mutations in PGRN, but also in the majority of patients with ALS and in 20-30% of pathologically confirmed Alzheimer's disease (AD) patients further suggests a role for the TDP-43 protein in a unifying neurodegenerative disease mechanism underlying these disorders. The recent identification of mutations in TDP-43 as a direct cause of neurodegeneration in sporadic and familial patients with ALS strongly supports this notion. Our working hypothesis is that the PGRN/TDP-43 axis plays a role in multiple neurodegenerative diseases including AD. In this project we will use both genetic and proteomic methods to help understand the role of PGRN and TDP-43 in AD and other neurodegenerative disorders. The Specific Aims of this project are: 1. To determine the role of genetic variants in PGRN and TARDBP (TDP-43) in the development and presentation of AD. We will perform genetic association studies of PGRN and TARDBP in Caucasian and African/American AD case-control populations and study the effect of common genetic variability on PGRN and TDP-43 expression levels, TDP-43 pathology and disease. 2. To identify novel PGRN and TDP-43 interacting proteins using somatic brain transgenic technology. We will use somatic brain transgenic technology to express dual affinity tagged PGRN and TDP-43 proteins in the mouse brain to identify binding partners of both PGRN and TDP-43. Proteins will be identified by proteomic technologies. Subsequent studies will validate whether PGRN/TDP-43 proteins interact in human brain tissue and are altered by disease state. The proposed studies are relevant to fully appreciate the contribution of genetic variants in PGRN and TARDBP to the development and presentation of AD. Identifying the protein networks of PGRN and TDP-43 will be critical for understanding the pathways of neurodegeneration mediated by PGRN and TDP- 43 and may lead to the identification of novel therapeutic targets.
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0.954 |
2012 — 2016 |
Rademakers, Rosa |
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. |
Ggggcc Hexanucleotide Repeat Expansions in Neurodegenerative Disease @ Mayo Clinic Jacksonville
DESCRIPTION (provided by applicant): The last few years have been extremely exciting for genetic research into the understanding of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two closely related devastating neurodegenerative disorders with overlapping clinical, genetic and neuropathologic features. In 2011, we identified a GGGGCC hexanucleotide repeat expansion in the non-coding region of C9ORF72 as the long- sought cause of FTD and ALS linked to chromosome 9p, further demonstrating the clinical and molecular overlap between these diseases. Genetic studies now suggest that this repeat expansion is the most common cause of familial FTD and ALS, explaining 10-20% of FTD and 25-40% of ALS families worldwide. This mutation also explains the disease in 1-5% of sporadic patients. What determines whether mutation carriers develop FTD and/or ALS and whether symptoms occur as early as 30 years of age or after the age of 70 has not yet been studied. Interestingly, in line with studies in other non-coding repeat expansion disorders, we showed that the repeat expansion leads to the formation of nuclear RNA foci, suggesting a possible toxic RNA gain-of-function disease mechanism. Our working hypothesis is that GGGGCC repeat expansions cause FTD and/or ALS, at least in part, through aberrant gene expression and alternative splicing changes that may result from the formation of these toxic RNA foci. The Specific Aims of this grant proposal are focused on 1) characterization of the variability in GGGGCC repeat size in blood, brain tissue and human cells in C9ORF72 mutation carriers and a detailed study of the effect of repeat size on clinical and pathological phenotypes; 2) identification of genetic modifiers of disease onset and/or presentation in patients carrying GGGGCC repeat expansions in C9ORF72; 3) study of the contribution of other GGGGCC repeats in the human genome to the development of FTD and ALS and 4) identification of gene expression and alternative splicing changes resulting from GGGGCC repeat expansions using high-throughput RNA sequencing in human brain tissue. The proposed studies are relevant to obtain a better understanding of the factors that contribute to the clinical and pathological variability associated with GGGGCC repeat expansions and have the ability to lead to the identification of mRNA targets implicated in FTD and ALS pathogenesis.
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1 |
2012 — 2016 |
Rademakers, Rosa |
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. |
Identification of Novel Parkinsonian Genes by Wholegenome @ Mayo Clinic Jacksonville
Classic linkage studies in multigenerational families have identified a number of genes that harbor muta- tions that cause neurodegeneration. The Mayo Clinic Udall Center investigators have successfully driven many of these studies and gene identification is one of the greatest strengths of our Center. Recently, the development of next-generation sequencing technologies has led to a shift in genetic studies, allowing the use of smaller pedigrees for which only a limited number of DNA samples are available and dramatically reducing the time it takes to identify new genes. Our Project sets out to use whole-genome sequencing in our unique collection of families with neurodegeneration to identify novel genes for Parkinsonian a-synucleinopathies (Aim 1) and tauopathies (Aim 2). Families are selected based on the availability of DNA samples from at least 3 affecteds, preferentially including an affected cousin-pair, autopsy confirmation of Lewy-body pathology or tau pathology, and exclusion of mutations in all known autosomal dominant Par- kinson's disease (PD) genes and the microtubule associated protein tau gene, MAPT. Novel variants will be prioritized based on the type of mutation and analyzed in a strictly defined manner. To determine whether rare and common variants in novel causal Parkinsonian genes confer risk to the general population of PD and progressive supranuclear palsy (PSP) patients, in-depth association studies of novel Parkinsonian genes will subsequently be performed (Aim 3). Coding variants identified by candi- date gene sequencing combined with haplotype-tagging variants across the candidate gene loci selected from public databases will be included. Significantiy associated variants will be further studied by assessing their influence on gene and protein expression, and the potential interaction with tau and a-synuclein biolo- gy. The discovery of novel genes and genetic risk factors, as proposed in this Project, will unquestionably contribute to a better understanding of the disease mechanism associated with tau and a-synuclein dys- function in Parkinsonian disorders. Moreover, the identification of novel Parkinsonian genes will further al- low the development of novel etiologic and symptomatic disease models in which new therapies can be evaluated. RELEVANCE (See instructions): This proposal is designed to identify novel causal genes in families with Parkinsonism and a-synuclein or tau pathology using whole-genome sequencing. The proposed studies will contribute to our understanding of and our ability to treat patients with Parkinsonism through improved patient diagnosis, the ability to de- velop novel etiologic disease models and an increased understanding of the disease mechanism associated with tau and a-synuclein dysfunction.
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1 |
2013 — 2016 |
Rademakers, Rosa |
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. |
Molecular Genetic Studies of Progranulin Regulators in Ftld and Als @ Mayo Clinic Jacksonville
DESCRIPTION (provided by applicant): Mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD). Individuals with GRN mutations have a 50% reduction in functional progranulin protein (PGRN) and also invariably display TDP-43 pathology (FTLD-TDP), indicating low PGRN levels as a potential initiator of TDP-43 dysfunction in FTLD. The identification of TDP-43 as the pathological protein, not only in patients with FTLD with mutations in GRN, but also in the majority of patients with ALS further suggests a role for TDP-43 in a unifying neurodegenerative disease mechanism underlying these disorders. Consequently, determining how PGRN levels are regulated in brain may lead to novel treatments and therapies for a range of neurodegenerative diseases. In the last few years, we and others have identified two PGRN regulators through genome-wide association studies: the uncharacterized transmembrane protein 106B (TMEM106B) and the multiligand receptor sortilin (SORT1). TMEM106B was identified as a risk factor for FTLD-TDP, with subsequent studies from our laboratory suggesting a role for TMEM106B in PGRN regulation. Of particular interest was the finding that a specific TMEM106B genetic variant (rs3173615 predicted to result in p.T185S) could significantly protect GRN mutation carriers from developing disease. We further identified SORT1 as a major regulator of PGRN levels in human plasma. Interestingly, SORT1 was independently identified as a neuronal receptor for PGRN. In preliminary data we now present an unpublished genome-wide quantitative trait locus analysis of GRN mRNA levels in human brain and identify TBC1 domain family, member 1 (TBC1D1) as yet another novel PGRN regulator. In this Project, we hypothesize that genetic variants in TMEM106B, SORT1 and TBC1D1 regulate PGRN levels and/or function in brain, thereby modifying disease risk, penetrance and presentation in TDP-43 proteinopathies. The Specific Aims are focused on 1) the functional characterization of the effect of the p.T185S protective variant on TMEM106B and PGRN using cell culture models, including primary cultures of mouse Pgrn knock-out and wild type hippocampal neurons, biochemical and molecular approaches and somatic gene transfer in mice using recombinant adeno-associated virus; 2) Systematic analyses of the role of genetic variants in TMEM106B, SORT1 and TBC1D1 in the development and presentation of FTLD and ALS by performing genetic association studies in extensive FTLD and ALS case- control populations using variants identified by whole-genome sequencing; and 3) determine the effect of newly identified TMEM106B, SORT1 and TBC1D1 variants on PGRN levels in vivo and in vitro. The proposed studies are relevant to fully appreciate the contribution of common and rare variants in TMEM106B, SORT1 and TBC1D1 to the development and presentation of FTLD and ALS and will lead to a greater understanding of PGRN regulation.
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1 |
2017 — 2019 |
Rademakers, Rosa |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
Genetic Discovery and Pathobiology of Frontotemporal Lobar Degeneration and Related Tdp-43 Proteinopathies @ Mayo Clinic Jacksonville
Our Research Program aims to provide new insights into disease pathogenesis and to identify novel targets for therapy through the discovery and subsequent study of novel disease genes implicated in frontotemporal lobar degeneration (FTLD) and related disorders. It is unique in that it spans the full spectrum of disease research from gene discovery to therapy development, which allows immediate validation and application of novel research findings. While significant progress has been made in recent years to improve our understanding of the genetics of FTLD and the pathologies underlying this collection of neurodegenerative diseases affecting the frontal and temporal brain regions, its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. FTLD represents 10-20% of all dementias and is clinically important because of its earlier age at onset compared to Alzheimer's disease (AD) and its dramatic impact on core human qualities, including personality, insight and verbal communication. The most common pathological subtype of FTLD is characterized by pathological aggregates of the TAR DNA-binding protein 43 (FTLD-TDP), which is also the main pathological protein in patients with amyotrophic lateral sclerosis (ALS). As part of our Research Program we previously identified mutations in progranulin (GRN) and repeat expansions in the chromosome 9 open reading frame 72 (C9ORF72) gene, the two most common causes of FTLD-TDP world-wide. We also identified the transmembrane protein 106 B gene (TMEM106B) as a major genetic modifier of disease onset and/or presentation in FTLD individuals with GRN and C9ORF72 mutations; however, other causal genes and modifying factors must exist. In this Research Program we will leverage our previous contributions to the field, novel resources and an extensive collection of patient samples to identify novel causal FTLD genes and genetic modifiers. Once new genes are identified, we will capitalize on the flexibility afforded by the R35 mechanism to immediately begin functional studies designed to expedite the translation of genetic discoveries to the patient's bedside. Through the discovery of novel FTLD disease genes and a better understanding of the factors that modify the expression of known disease genes such as GRN and C9ORF72, our Research Program will allow more accurate and earlier diagnosis, provide much needed guidance for clinicians involved in genetic counseling of mutation families, guide the inclusion of patients for future clinical trials and provide important novel insight into FTLD pathobiology. Our Program will also advance the development of biomarkers associated with disease phenotype or progression and provide novel targets for therapies.
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1 |
2017 — 2021 |
Rademakers, Rosa |
UG3Activity Code Description: As part of a bi-phasic approach to funding exploratory and/or developmental research, the UG3 provides support for the first phase of the award. This activity code is used in lieu of the UH2 activity code when larger budgets and/or project periods are required to establish feasibility for the project. UH3Activity Code Description: The UH3 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the UH2 mechanism. Although only UH2 awardees are generally eligible to apply for UH3 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under UH2. |
Whole Genome Sequencing Consortium On Frontotemporal Dementia With Underlying Tdp-43 Pathology @ Mayo Clinic Jacksonville
This UG3/UH3 proposal aims to identify and functionally validate novel genes for frontotemporal lobar degeneration with underlying TDP-43 pathology (FTLD-TDP) through the establishment of an international Sequencing Consortium and an interdisciplinary team of investigators. FTLD comprises a genetically, clinically and pathologically heterogeneous collection of neurodegenerative diseases affecting the frontal and temporal brain regions. Its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. FTLD represents 10-20% of all dementias and is clinically important because of its earlier age at onset compared to Alzheimer's disease (AD) and its dramatic impact on core human qualities, including personality, insight and verbal communication. FTLD-TDP represents the most common FTLD pathological subtype and two major genes have previously been implicated in its genetic etiology, both identified by our study team: mutations in progranulin (GRN) and repeat expansions in the chromosome 9 open reading frame 72 (C9ORF72). However, despite these major advances the cause of the disease in more than 50% of FTLD-TDP patient remains unexplained and much of the pathophysiology underlying FTLD-TDP unknown. In the UG3 phase of this proposal, we will collect biospecimens and detailed phenotypic data from patients with pathologically confirmed FTLD-TDP and patients with clinical diagnoses of semantic variant primary progressive aphasia (svPPA) and frontotemporal dementia with amyotrophic lateral sclerosis (FTD/ALS), highly likely to have TDP-43 pathology from more than 30 sites world- wide (Aim 2). Whole genome sequencing (WGS) will be performed on 625 new FTLD patients and combined with publically available WGS data on 3000 controls to comprise a genetic replication cohort. In Aims 1a+b, WGS data from the replication cohort and a previously generated discovery cohort (500 FTLD-TDP patients and 1000 controls) will be processed through an analytical pipeline developed in collaboration with other FTD consortia. Statistical analyses will subsequently nominate candidate FTLD genes and variants. In the UH3 phase of this proposal, we will prioritize and validate candidate FTLD genes using integrative genomic, transcriptomic, proteomic and statistical analyses in vivo using tissues or cells isolated from FTLD-TDP patients and controls (Aim 3) and ex vivo using human induced pluripotent stem cell models using integrative transcriptomic, proteomic, and high- content imaging assays (Aim 4). Through the discovery of novel FTLD-TDP disease genes we will provide important novel insight into FTLD-TDP pathobiology, advance the development of biomarkers and provide novel targets for therapies.
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1 |
2019 — 2021 |
Rademakers, Rosa |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Genetics Core
ABSTRACT ? ARTFL LEFFTDS Longitudinal FTLD: GENETICS CORE The overarching goal of the Genetics Core is the accurate and timely generation, annotation, interpretation and sharing of state-of-the art genetic data on all frontotemporal lobar degeneration (FTLD) patients and blood relatives enrolled in ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) to support FTLD research within and outside of the ALLFTD Program. Genetic characterization of this unique cohort is critically important to test hypotheses and interpret research findings obtained in the other ALLFTD Cores and Projects and will be invaluable to future FTLD gene discovery efforts within the larger research community. The work proposed in this Core is highly complementary and non-overlapping with currently ongoing NIH-funded FTLD sequencing efforts, which will be leveraged to enhance the genetic characterization of our participant cohorts. More than 1,100 unique individuals have been enrolled in ARTFL and LEFFTDS since their inception in 2014 and an additional 1,600 unique individuals are expected to be enrolled as part of the ALLFTD protocol. Consequently, DNA of at least 2,700 individuals will be available for genetic studies, making this an unprecedented resource. Most notably, on all 2,700 subjects, the Genetics Core will: generate genome-wide single nucleotide variant (SNP) data; perform targeted mutation screening of ~300 neurodegenerative disease genes; determine presence or absence of causal mutations in known disease genes; and integrate genetic data in the form of polygenic risk scores (PGRS) for downstream analyses in the Projects. These important goals are achieved through the following Specific Aims: 1) Perform genetic analyses to determine ethnicity and relatedness between ALLFTD participants. Genotyping using the Infinium Omni2.5Exome-8 Kit will be performed in all newly ascertained ALLFTD participants (n=1,600) and combined with previously obtained genotype data (n=1,100) to determine the ethnicity and relatedness between ALLFTD participants, to call copy-number variants (CNVs) and to calculate PGRS; 2) Perform targeted mutation analysis in ALLFTD participants. We will follow an efficient, step-wise, approach to genetically characterize ALLFTD participants, including C9orf72 and ATXN2 repeat expansion testing, targeted gene sequencing of ~300 neurodegenerative disease genes with sequence validation and manual curation of observed variants using American College of Medical Genetics and Genomics guidelines, and whole-genome sequencing and analysis of newly ascertained genetically unexplained familial FTLD patients; and 3) Generate PGRS for ALLFTD participants. Distinct datasets from published genome-wide association studies will be used to generate PGRS in study participants for use in the Projects, including PGRS for individual neurodegenerative diseases and PGRS that reflect related pathologies such as immunological disorders. As our sample size increases we will further derive PGRS from genomic data generated as part of ALLFTD, especially for FTLD clinical subtypes.
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0.954 |