Alterations in synaptic growth and lipid-raft organization in a fly MLIV model

果蝇 MLIV 模型中突触生长和脂筏组织的变化

基本信息

批准号：
9222813
负责人：
KARTIK VENKATACHALAM
金额：
$ 33.25万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222813
关键词：
Address Affect Age Biochemical Biological Process Brain Brain imaging Cations Cell membrane Cells Childhood Cholesterol Clinical Trials Corpus Callosum Data Defect Development Disease Disease Outcome Drosophila genus Drug usage Enzymes Esterification Esters Exhibits Functional disorder Ganglioside Sialidase Deficiency Disease Generations Genetic Goals Growth Hereditary Disease Homologous Gene JUN gene Larva Link Lysosomal Storage Diseases Lysosomes Malignant Neoplasms Membrane Membrane Microdomains Mendelian disorder Methodology Mitogen-Activated Protein Kinases Modeling Molecular Mutation Nature Nerve Degeneration Neurobiology Neurologic Neurological outcome Neuromuscular Junction Neuronal Dysfunction Neurons Ophthalmology Patients Phenotype Phosphotransferases Process Proteins Publishing Resolution Signal Transduction Spielmeyer-Vogt Disease Synapses Testing Therapeutic Vesicle axon growth cognitive development cohort esterase fly imaging study in vivo insight late endosome lipoprotein cholesterol loss of function mutation neuropathology new technology novel pleiotropism prevent public health relevance receptor binding therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Many lysosomal storage diseases (LSDs) cause childhood-onset neurodegeneration leading to profound psychomotor retardation and ophthalmological abnormalities. In general, LSDs are notoriously difficult to treat because although these diseases are monogenic in origin, they typically affect a host of cellular signaling cascades and cell biological processes. The pleiotropy associated with LSDs prevents the development of suitable therapeutic strategies that simultaneously target the multiple disease outcomes. Moreover, it is becoming increasingly clear that LSDs are also characterized by neurodevelopmental abnormalities such as diminished axonal development in the cortex and corpus callosum. Unfortunately, the mechanistic basis for these neuronal defects associated with LSDs remain poorly understood. The overarching goal of this proposal is to address these conceptual gaps using a Drosophila model of an LSD called mucolipidosis type IV (MLIV) that arises from loss of function mutations in a lysosomal Ca2+ channel called TRPML1. We previously established that the fly TRPML1 homolog, TRPML, is a late-endosomal/amphisomal Ca2+ channel that drives the fusion of these vesicles with lysosomes. Here, we will leverage the genetic tractability of the Drosophila to address the critical mechanistic questions regarding the neuropathology of LSDs. In Aim 1, we will test the hypothesis that loss of TRPML results in alterations in the organization of cholesterol-enriched ordered membrane microdomains called lipid rafts. Because lipid rafts are critical for the functioning of a plethora of cellular signalig processes, alterations in the stability of these domains could provide a mechanistic explanation for the pleiotropy associated with lysosomal dysfunction. In Aim 2, we will test the hypothesis that TRPML promotes synaptic growth by activating developmental c-Jun Kinase (JNK) signaling in neurons. Interestingly, diminished JNK activation results in hypoplasia and agenesis of axonal tracts of the cortex and corpus callosum. Therefore, decreased JNK activation following lysosomal dysfunction signaling may be the molecular explanation for why LSDs are characterized by axonal growth defects. If successful, these studies should provide us with mechanistic insight into some of the common neurological outcomes associated with lysosomal dysfunction and also aid in the establishment of concepts for therapeutically targeting the neurological sequelae of LSDs.

描述（由申请人提供）：许多溶酶体储存疾病（LSDS）导致儿童期神经变性导致深刻的心理障碍和眼科异常。通常，众所周知，LSD很难治疗，因为尽管这些疾病的起源是单基因的，但它们通常会影响大量的细胞信号传导级联和细胞生物学过程。与LSDS相关的多效性阻止了适当的治疗策略的发展，这些治疗策略同时针对多种疾病结果。此外，越来越清楚的是，LSD也具有神经发育异常的特征，例如皮层和call体的轴突发育减少。不幸的是，与LSD相关的这些神经元缺陷的机械基础仍然知之甚少。该提案的总体目标是使用称为粘脂异常IV（MLIV）的LSD的果蝇模型来解决这些概念差距，该模型是由称为TRPML1的溶酶体Ca2+通道中功能突变的丧失引起的。我们先前确定Fly TRPML1同源物TRPML是一种晚期 - 内体/两栖CA2+通道，可驱动这些囊泡与溶酶体的融合。在这里，我们将利用果蝇的遗传障碍性解决有关LSDS神经病理学的关键机理问题。在AIM 1中，我们将检验以下假设：TRPML的丧失会导致富含胆固醇的有序膜微区的组织变化，称为脂质筏。由于脂质筏对于大量细胞信号过程的功能至关重要，因此这些结构域的稳定性改变可以为与溶酶体功能障碍相关的多效率提供机械解释。在AIM 2中，我们将检验以下假设：TRPML通过激活神经元中的发育C-JUN激酶（JNK）信号来促进突触生长。有趣的是，JNK激活减少会导致皮质和call体的轴突症的发育不全和轴突症的发育症。因此，在溶酶体功能障碍信号传导后JNK激活降低可能是分子解释，说明LSD为何以轴突生长缺陷为特征。如果成功的话，这些研究应为我们提供对与溶酶体功能障碍相关的某些常见神经系统结局的洞察力，并有助于建立概念，以靶向LSD的神经系统后遗症。