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

• 批准号: 10609928
• 负责人: Reymundo Lozano
• 金额: $ 27.15万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609928
• 关键词: Academic achievement; Age; Alzheimer' 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; Lipids; Macrophage; 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; 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; 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; medical schools; metabotropic glutamate receptor 5; mitochondrial dysfunction; neurotoxic; novel; polyglycine; polypeptide; programs; protein aggregation; protein degradation; proteostasis; response; sex; single nucleus RNA-sequencing; skills; stem; therapeutic target; transcriptome; transcriptome sequencing

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

项目概要/摘要 候选人。洛扎诺博士是一位早期职业医师兼科学家，他凭借自己的学术成就 临床和基础科学方面的成就和多样化培训，以制定独立的研究计划。 通过他的工作，他发展了遗传学和分子生物学以及临床的实验室技能 研究共同构成了这个正在进行的项目的基础。 职业发展。洛扎诺博士的总体长期职业目标是领导一个有意义且可持续的组织 研究计划将使他能够继续成为该领域成熟且独立的研究者 脆性 X 相关疾病。这些目标将通过严格的指导来实现（艾莉森·戈特博士） （导师）、张斌（联合导师）和乔治·迪亚兹（联合导师））、有意义的合作和个性化 教学机制，在本申请中概述。 制度环境。伊坎学院遗传学与基因组科学系 西奈山的医学是一个世界一流的基础科学和临床混合项目，提供基础广泛的 教学、研究和临床服务计划。教师都是分子应用领域的专家 用于研究遗传疾病的生物学、数据科学和体细胞方法。环境 该部门提供的课程非常适合执行本申请中概述的研究。 研究项目。那里 在 明白了。 这 假设 这 在 核糖核酸 转录组 机制， 到 和 硬化症/额颞叶 福克斯塔斯 决定 目前尚无针对神经退行性疾病（NDD）的有效治疗方法。 为了开发潜在的治疗靶点，必须更清楚潜在的生物学机制 脆性 X 相关震颤/共济失调综合征 (FXTAS) 提供了深入了解 NDD 疾病的病理机制源于明确的遗传病因。整体 是蛋白质清除缺陷因多肽和产生的 mRNA-FMR1 而加剧 CGG 扩张。这导致神经元反应驱动的泛素蛋白沉积增加 包涵体，导致细胞功能障碍、反应性炎症小胶质细胞并最终导致神经退行性变 测序（批量和单核）将用于定性和定量检查 在死后的人体组织中。由于 NDD 涉及复杂且相互交织的生物 将采用公正且无假设的方法来发现关键分子途径。 为了识别 NDDS 中的聚合病理过程，将交叉检查新颖的 FXTAS 数据集 阿尔茨海默病、帕金森病和肌萎缩侧索硬化症的可用数据集 痴呆症。这项研究不仅有可能确定驱动的关键机制 发病机制将促进生物标志物和治疗靶点的发现，但也 通过与其他 NDD 的交叉检验方法，找出疾病最核心的途径。 , t 哦 。 ds f

项目成果

Latent Class Analysis Identifies Distinctive Behavioral Subtypes in Children with Fragile X Syndrome.

潜在类别分析可识别脆性 X 综合征儿童的独特行为亚型。

• DOI: 10.1007/s10803-022-05821-7
• 发表时间: 2024
• 期刊: Journal of autism and developmental disorders
• 影响因子: 3.9
• 作者: Kaufmann,WalterE;Raspa,Melissa;Bann,CarlaM;Gable,JuliaM;Harris,HollyK;Budimirovic,DejanB;Lozano,Reymundo;FORWARDConsortium
• 通讯作者: FORWARDConsortium

Autosomal Recessive Limb-Girdle Muscular Dystrophy-3: A Case Report of a Patient with Autism Spectrum Disorder.

• DOI: 10.3390/genes14081587
• 发表时间: 2023-08-05
• 期刊: GENES
• 影响因子: 3.5
• 作者: Lewis, Sivan;Woroch, Amy;Hatch, Mary Kate;Lozano, Reymundo
• 通讯作者: Lozano, Reymundo

Exploring Parents' Concerns Regarding Long-Term Support and Living Arrangements for Their Children with Fragile X Syndrome.

• DOI: 10.3390/genes13091654
• 发表时间: 2022-09-15
• 期刊: Genes
• 影响因子: 3.5

Observable Symptoms of Anxiety in Individuals with Fragile X Syndrome: Parent and Caregiver Perspectives.

• DOI: 10.3390/genes13091660
• 发表时间: 2022-09-16
• 期刊: Genes
• 影响因子: 3.5

The Impact of the COVID-19 Pandemic on School-Aged Children with Fragile X Syndrome.

• DOI: 10.3390/genes13091666
• 发表时间: 2022-09-17
• 期刊: Genes
• 影响因子: 3.5