FXTAS Key Molecular Pathways Converge with Other Neurodegenerative Disorders

FXTAS 关键分子通路与其他神经退行性疾病的融合

基本信息

批准号：
10429040
负责人：
Reymundo Lozano
金额：
$ 27.09万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10429040
关键词：
Academic achievement Age Alzheimer&apos s Disease Area Ataxia Automobile Driving Autopsy Basic Science Biological Brain Brain region C9ORF72 CGG repeat expansion Cell Nucleus Cell physiology Cells Chronic Clinical Clinical Research Clinical Sciences Clinical Services Cluster Analysis Collaborations Complex Data Science Data Set Degradation Pathway Dementia Deposition Disease Environment Eukaryota FMR1 FMRP FXTAS Faculty Foundations Fragile X Syndrome Gene Expression Gene Expression Profiling Genetic Genetic Diseases Genetic Predisposition to Disease Genetic study Goals Hybrids Immunohistochemistry Impaired cognition Individual Inflammation Inflammatory Instruction Laboratories Lateral Lead Lipids Malignant Neoplasms Mediating Mental Depression Mentors Mentorship Messenger RNA Metabolic Methods Microglia Molecular Molecular Biology Motor Cortex Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neurosciences Parkinson Disease Parkinsonian Disorders Pathogenesis Pathologic Pathologic Processes Pathway Analysis Pathway interactions Peptides Pharmaceutical Preparations Phenotype Physicians Prefrontal Cortex Process Proteins Proteome RNA Research Research Personnel Research Project Grants Research Training Resolution Role Sampling Scientist Sclerosis Signal Transduction Somatic Cell System Time Tissues Training Transcript Transcription Alteration Tremor Tremor/Ataxia Syndrome Ubiquitin Ubiquitination Western Blotting Work base behavioral disinhibition biomarker discovery brain tissue career career development cell type cytokine differential expression effective therapy excitatory neuron excitotoxicity genome sciences human tissue insight interdisciplinary approach macrophage medical schools metabotropic glutamate receptor 5 mitochondrial dysfunction neurotoxic novel polyglycine polypeptide programs protein aggregation protein degradation proteostasis response sex skills stem therapeutic target transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT THE CANDIDATE. Dr. Lozano is an early career physician-scientist, who has drawn on his academic achievement and diverse training in clinical and basic science to develop an independent research program. Through his work, he has developed laboratory skills in genetics and molecular biology, as well as clinical research which together form the foundations of this ongoing project. CAREER DEVELOPMENT. Dr. Lozano's overall long-term career goal is to lead a meaningful and sustainable research program that will allow him to remain a well-established and independent investigator in the area of Fragile X-related disorders. These goals will be accomplished through intense mentorship (Drs. Alison Goate (mentor), Bin Zhang (co-mentor), and George Diaz(co-mentor)), meaningful collaborations, and personalized didactic mechanisms, which are outlined in this application. INSTITUTIONAL ENVIRONMENT. The Department of Genetics & Genomic Sciences at the Icahn School of Medicine at Mount Sinai is a hybrid world-class basic science and clinical program that offers a broad-based program of instruction, research, and clinical services. The faculty are experts in the application of molecular biology, data science, and somatic cell approaches for the study of genetic diseases. The environment provided in the department is ideal for the execution of the studies outlined in this application. RESEARCH PROJECT. There In understood. the hypothesis the in RNA transcriptome mechanisms, To with sclerosis/Frontotemporal FXTAS determine are currently no effective treatments for neurodegenerative disorders (NDDs). order to develop potential therapeutic targets the underlying biological mechanisms mus be more clearly Fragile X-associated tremor/ataxia syndrome (FXTAS) ffers an opportunity to gain insights into pathological mechanisms for an NDD disorder that stems from a defined genetic etiology. The overall is that protein clearance deficits are exacerbated by polypeptides and mRNA-FMR1 produced from CGG expansion. This results in neuronal response-driven increases in ubiquitin proteins that are deposited inclusions, leading to cell dysfuction, reactive inflammatory microglial and eventually neurodegeneration sequencing (bulk and single nuclei) will be used to qualitatively and quantitatively examine the in postmortem human tissue. Since NDDs involve complex and intertwined biological an unbiased and hypothesis-free approach for key molecular pathways discovery will be applied. identify the converging pathologica l processes in NDDS, the novel FXTAS datasets will be cross-examined available datasets of Alzheimer's Disease, Parkinson Disease and amyotrophic lateral ementia . This tudy has the potential to not only identify critical mechanisms driving pathogenesis that would acilitate the discovery of biomarkers and therapeutic targets but also pathways most central to disease through a cross-examination approach with other NDDs. , t o . d s f

项目摘要/摘要候选人。 Lozano博士是早期的职业医师科学家，他的学术训练在临床和基础科学方面的成就和多样化的培训，以制定独立研究计划。通过他的工作，他发展了遗传学和分子生物学的实验室技能以及临床研究共同构成了这个正在进行的项目的基础。职业发展。 Lozano博士的整体长期职业目标是领导有意义且可持续的研究计划将使他能够在该领域保持良好和独立的调查员脆弱的X相关疾病。这些目标将通过激烈的指导来实现（Alison Goate博士（导师），张张（Co-Insor）和乔治·迪亚兹（George Diaz）（联合学）），有意义的合作和个性化该应用中概述的教学机制。机构环境。伊坎学校的遗传学和基因组科学系西奈山的医学是一项混合世界一流的基础科学和临床计划，可提供广泛的基础教学，研究和临床服务计划。该教师是分子应用的专家生物学，数据科学和遗传疾病研究的体细胞方法。环境部门提供的是执行本申请中概述的研究的理想选择。研究项目。那里在理解。这假设这在 RNA 转录组机制，到和硬化/额颞 fxtas 决定目前尚无神经退行性疾病（NDD）的有效治疗方法。为了开发潜在的治疗靶标的基本生物学机制MUS更清楚脆弱的X相关震颤/共济失调综合征（FXTA）有机会获得洞察力 NDD疾病的病理机制源自定义的遗传病因。总体是蛋白质清除率缺陷被多肽和由多肽和由MRNA-FMR1加剧而加剧 CGG扩展。这导致神经元反应驱动的泛素蛋白的增加夹杂物导致细胞功能障碍，反应性炎症小胶质细胞和最终神经退行性测序（散装和单核）将用于定性和定量检查在死后人体组织中。由于NDD涉及复合和交织的生物学将采用一种无偏见的无假设方法，用于发现关键分子途径的发现。识别NDD中的融合病理学过程，新颖的FXTA数据集将进行盘问可用的阿尔茨海默氏病，帕金森病和肌萎缩性侧面的数据集 ementia。这种tudy不仅有可能识别驱动的关键机制将生物标志物和治疗靶标的发现的发病机理，也将通过与其他NDD的盘问方法最重要的途径。，t o 。 D s f