Genetic Discovery and Pathobiology of Frontotemporal Lobar Degeneration and Related TDP-43 Proteinopathies
额颞叶变性及相关 TDP-43 蛋白病的遗传发现和病理学
基本信息
- 批准号:9156742
- 负责人:
- 金额:$ 88.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Advanced DevelopmentAffectAgeAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisBrain regionC9ORF72ClinicalClinical TrialsCollectionCommunicationDementiaDiagnosisDiseaseDisease ProgressionEarly DiagnosisFamilyFrontotemporal Lobar DegenerationsFutureGene-ModifiedGenesGeneticGenetic CounselingGenetic TranslationHumanIndividualIntegral Membrane ProteinMedicalMutationNeurodegenerative DisordersOnset of illnessPGRN genePathogenesisPathologicPathologyPathway interactionsPatientsPersonalityProteinsResearchResearch DesignResourcesSamplingValidationaccurate diagnosisbiomarker developmentdisease phenotypeearly onsetflexibilitygene discoveryimprovedinsightnew therapeutic targetnovelprogramsprotein TDP-43therapy development
项目摘要
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.
我们的研究计划旨在通过发现和随后研究与额颞叶变性(FTLD)和相关疾病有关的新疾病基因,为疾病发病机制提供新的见解,并确定新的治疗靶点。它的独特之处在于,它跨越了从基因发现到治疗开发的所有疾病研究领域,允许立即验证和应用新的研究成果。虽然近年来在提高我们对FTLD的遗传学和影响额叶和颞叶脑区的神经退行性疾病的病理基础的了解方面取得了重大进展,但其诊断可能具有挑战性,并且没有减缓或阻止疾病进展的治疗方法,这突显了FTLD患者巨大的未得到满足的医疗需求。FTLD占所有痴呆症的10%-20%,具有重要的临床意义,因为与阿尔茨海默病(AD)相比,它的发病年龄更早,而且它对人格、洞察力和语言交流等核心人类素质产生了巨大影响。FTLD最常见的病理亚型是TAR DNA结合蛋白43(FTLD-TDP)的病理性聚集,它也是肌萎缩侧索硬化症(ALS)患者的主要病理蛋白。作为我们研究计划的一部分,我们之前发现了原颗粒(GRN)突变和9号染色体开放阅读框架72(C9ORF72)基因的重复扩展,这是全球范围内FTLD-TDP的两个最常见的原因。我们还发现跨膜蛋白106B基因(TMEM106B)是携带GRN和C9ORF72突变的FTLD患者发病和/或表现的主要遗传修饰因子;然而,必须存在其他原因基因和修饰因子。在这项研究计划中,我们将利用我们以前在该领域的贡献、新的资源和大量的患者样本来确定新的致病FTLD基因和遗传修饰物。一旦确定了新的基因,我们将利用R35机制提供的灵活性,立即开始旨在加快将基因发现转化到患者床边的功能研究。通过发现新的FTLD疾病基因和更好地了解影响已知疾病基因表达的因素,如GRN和C9ORF72,我们的研究计划将使更准确和更早的诊断成为可能,为参与突变家族遗传咨询的临床医生提供急需的指导,指导纳入未来临床试验的患者,并为FTLD病理生物学提供重要的新见解。我们的计划还将推进与疾病表型或进展相关的生物标记物的开发,并为治疗提供新的靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Rosa Rademakers', 18)}}的其他基金
Whole genome sequencing consortium on Frontotemporal dementia with underlying TDP-43 pathology
针对具有潜在 TDP-43 病理学的额颞叶痴呆的全基因组测序联盟
- 批准号:
9977807 - 财政年份:2017
- 资助金额:
$ 88.86万 - 项目类别:
Whole genome sequencing consortium on Frontotemporal dementia with underlying TDP-43 pathology
针对具有潜在 TDP-43 病理学的额颞叶痴呆的全基因组测序联盟
- 批准号:
10263328 - 财政年份:2017
- 资助金额:
$ 88.86万 - 项目类别:
Whole genome sequencing consortium on Frontotemporal dementia with underlying TDP-43 pathology
针对具有潜在 TDP-43 病理学的额颞叶痴呆的全基因组测序联盟
- 批准号:
9751999 - 财政年份:2017
- 资助金额:
$ 88.86万 - 项目类别:
Molecular genetic studies of progranulin regulators in FTLD and ALS
FTLD 和 ALS 中颗粒体蛋白前体调节因子的分子遗传学研究
- 批准号:
8842721 - 财政年份:2013
- 资助金额:
$ 88.86万 - 项目类别:
Molecular genetic studies of progranulin regulators in FTLD and ALS
FTLD 和 ALS 中颗粒体蛋白前体调节因子的分子遗传学研究
- 批准号:
8652520 - 财政年份:2013
- 资助金额:
$ 88.86万 - 项目类别:
Molecular genetic studies of progranulin regulators in FTLD and ALS
FTLD 和 ALS 中颗粒体蛋白前体调节因子的分子遗传学研究
- 批准号:
9058616 - 财政年份:2013
- 资助金额:
$ 88.86万 - 项目类别:
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