Evaluation of a novel NLK function in lysosome biogenesis and neurodegenerative diseases

溶酶体生物合成和神经退行性疾病中新的 NLK 功能的评估

基本信息

批准号：
10616786
负责人：
Janghoo Lim
金额：
$ 80.82万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616786
关键词：
ALS patients Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Animal Model Antisense Oligonucleotides Autophagocytosis Behavioral Behavioral Assay Biochemical Biogenesis Bioinformatics Cortical Cord Cytoplasm Cytoplasmic Inclusion DNA-Binding Proteins Data Development Disease Disease Progression Effectiveness Etiology Evaluation Frontotemporal Dementia Future Gene Expression Genetic Genetic Transcription Goals Lysosomes Mediating Molecular Motor Motor Neurons Mus Nervous System Neurodegenerative Disorders Neuroglia Neurons Nuclear Onset of illness Organelles Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Phosphorylation Play Pre-Clinical Model Protein-Serine-Threonine Kinases Proteins Quality Control Regulation Research Role Serine Spinal Cord TDP-43 aggregation Testing Therapeutic Therapeutic Intervention cell type frontotemporal lobar dementia amyotrophic lateral sclerosis improved in utero in vivo in vivo Model insight motor deficit mouse model nemo-like kinase neuropathology novel novel strategies pharmacologic phosphoproteomics postnatal prevent protein TDP-43 protein aggregation response therapeutic evaluation therapeutically effective transcription factor transcriptomics

项目摘要

1R01AG074609-01 Janghoo Lim In the majority of neurodegenerative diseases, including Alzheimer’s disease (AD), one or more proteins aggregate over the course of disease progression. In the case of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), AD, and other AD-related dementias (ADRDs), cytoplasmic inclusions of transactive response DNA binding protein 43 kDa (TDP-43) are observed in a large percentage of patients with sporadic and familial forms of disease. This aberrant accumulation of cytoplasmic TDP-43 is thought to underlie gain of toxic functions and exacerbate loss of nuclear function pathogenic mechanisms; therefore, preventing the formation or promoting the clearance of these inclusions may be an effective therapeutic approach for TDP-43 proteinopathies, such as AD and ADRDs. Currently, there are no therapeutics that effectively alter the course of most neurodegenerative diseases associated with TDP-43 proteinopathy. We have recently identified Nemo-like kinase (Nlk) as a negative regulator of the lysosome, a key organelle involved in cellular protein quality control that is capable of clearing toxic aggregated proteins. This proposal aims to better understand the basic molecular mechanism of Nlk’s regulation of lysosome gene expression in the nervous system and to test the modulatory effects of Nlk in ADRD animal models of TDP-43 aggregation. We propose the following three specific aims. Aim 1 will employ unbiased and targeted approaches to uncover fundamental mechanistic insights into the regulation of lysosome gene expression by Nlk in neurons. Aim 2 will determine which cell types mediate the function of Nlk in the regulation of the lysosome and TDP-43 proteinopathy in the nervous system in vivo using wild-type and TDP-43 animal models. Aim 3 will expand the scope of the proposed study to understand the therapeutic implications of Nlk reduction in animal models of TDP-43 aggregation through genetic and pharmacological reduction of Nlk levels at varying times in adulthood in vivo. In doing so, we will test the effect of Nlk reduction in the control of the onset and progression of pathological and motor behavioral changes in TDP-43 mouse models of ADRD. Aims 2 and 3 will provide critical proof-of-principle evidence regarding the effectiveness of lysosomal modulation in pre-clinical models of protein aggregation disorders. Together, this project will reveal novel molecules involved in lysosomal regulation in neurons that may be potential targets in the treatment of various neurodegenerative diseases, including AD and several AD-related disorders.

1R01AG074609-01 Janghoo Lim 在包括阿尔茨海默氏病（AD）在内的大多数神经退行性疾病中，一种或多种蛋白质在整个疾病进展过程中聚集。在肌萎缩性外侧硬化症（ALS）和额颞痴呆（FTD），AD和其他与AD相关的痴呆症（ADRDS）的情况下，在大百分比患者和一家人中，经过透射反应DNA结合蛋白43 kDa（TDP-43）的细胞质夹杂物被观察。细胞质TDP-43的这种异常积累被认为是有毒功能的增益和加剧核功能致病机制的丧失的基础。因此，防止形成或促进清除这些夹杂物可能是TDP-43蛋白质病（例如AD和ADRD）的有效治疗方法。当前，没有治疗剂有效地改变与TDP-43蛋白质病有关的大多数神经退行性疾病的过程。我们最近已经确定了溶酶体的阴性调节剂，溶酶体是一种参与细胞蛋白质质量控制的关键细胞器，能够清除有毒聚集的蛋白质。该建议旨在更好地了解NLK调节神经系统中溶酶体基因表达的基本分子机制，并测试NLK在TDP-43聚集的ADRD动物模型中NLK的调节作用。我们提出以下三个特定目标。 AIM 1将采用公正和靶向的方法来揭示NLK通过NLK在神经元中调节溶酶体基因表达的基本机械洞察。 AIM 2将通过使用野生型和TDP-43动物模型来确定哪种细胞类型介导了NLK在体内神经系统中溶酶体和TDP-43蛋白质病的调节中的功能。 AIM 3将扩大拟议研究的范围，以了解NLK降低TDP-43聚集动物模型的治疗意义，这是通过遗传和药物降低NLK水平在体内变化时的NLK水平的降低。在此过程中，我们将测试NLK减少在ADRD的TDP-43小鼠模型中病理和运动行为变化的发作和进展中的效果。 AIM 2和3将提供有关溶酶体调节蛋白聚集疾病临床前模型中溶酶体调节有效性的关键原则证据。总之，该项目将揭示神经元中溶酶体调节涉及的新分子，这可能是治疗各种神经退行性疾病的潜在靶标，包括AD和几种与AD相关的疾病。