Evaluating dendritic DJ-1 targets as a framework for identifying pharmacotherapies for TSC-related neurological disorders

评估树突状 DJ-1 靶点作为确定 TSC 相关神经系统疾病药物治疗的框架

• 批准号: 10629909
• 负责人: Farr Niere
• 金额: $ 13.94万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629909
• 关键词: Affect; Anatomy; Anxiety; Anxiety Disorders; Behavioral; Behavioral Assay; Biological; Biological Models; Brain Diseases; Calcium Channel; Calcium Channel Agonists; Cell membrane; Central Nervous System; Chronic; Communication; Complex; Data; Dendrites; Development; Diagnosis; Disease; Environment; Epilepsy; Exhibits; FRAP1 gene; Frequencies; Functional disorder; General Population; Genetic; Genetic Diseases; Historically Black Colleges and Universities; Hyperactivity; Individual; Injections; Institution; Investigation; Knockout Mice; L-Type Calcium Channels; Link; Literature; Mediating; Medical; Mental disorders; Messenger RNA; Molecular; National Institute of Neurological Disorders and Stroke; Neurobiology; Neurons; Neurosciences Research; Newborn Infant; North Carolina; PARK7 gene; Pathologic; Pathway interactions; Patients; Peripheral; Pharmacotherapy; Phosphotransferases; Pre-Clinical Model; Protein Biosynthesis; Protein Synthesis Inhibition; Proteins; RNA-Binding Proteins; Regulation; Repression; Research; Research Personnel; Rodent Model; Science; Seizures; Signal Pathway; Signal Transduction; Social Phobia; Students; Subcellular structure; Symptoms; Synapses; TSC1 gene; TSC2 gene; Testing; Therapeutic; Translational Repression; Translations; Tuberous Sclerosis; Universities; Work; anxiety-like behavior; associated symptom; autism spectrum disorder; comorbidity; efficacy evaluation; graduate student; improved; insight; link protein; loss of function mutation; mRNA Translation; mouse model; nervous system disorder; neuropsychiatric disorder; novel; overexpression; pharmacologic; programs; protein expression; synaptic function; synaptic inhibition; tool; trafficking; undergraduate student

PROJECT SUMMARY/ABSTRACT Epilepsy, autism spectrum disorder, and anxiety disorders are highly comorbid. Indeed, this is the case in TSC. Despite the importance of this problem, the molecular connection among these disorders are poorly understood. Importantly, pharmacological therapies that can mitigate these comorbid symptoms are lacking. Because of these medical needs, we are taking advantage of TSC as a model system to gain a better understanding of the mechanisms linking epilepsy, autism and anxiety disorders. The mammalian/mechanistic target of rapamycin (mTOR) is hyperactive in epilepsy, autism, anxiety disorders, and TSC. A kinase that regulates protein synthesis, our previous work has demonstrated that perturbations in mTOR greatly affects the levels of proteins at synapses—critical subcellular structures that mediate communication among neurons. Of note, these comorbid disorders manifest synaptic dysfunction. Moreover, we have discovered that mTOR equally induces and inhibits synaptic protein levels. Thus, chronic, overactive mTOR may perpetually keep synapses in a state of disease causing some proteins to be overexpressed and others to be underexpressed. Unlike the proteins that are overexpressed when mTOR is hyperactive, the identity of the underexpressed proteins and how their levels are regulated are relatively unknown. Insights into the mechanisms underlying the diminished expression of proteins when mTOR is hyperactive is essential to gain a better understanding of how these comorbid disorders are molecularly linked. We have recently found that mTOR controls the levels of synaptic DJ-1, a newly-identified RNA binding protein that represses the translation of its associated mRNAs. Thus, DJ-1 may mediate the underexpression of proteins at or near the synapse when mTOR is active. Two of these underexpressed proteins whose mRNAs associated with DJ-1 are CaV1.2 and alpha2delta2—L-type voltage-dependent calcium channel (L-VDCC) subunits implicated in epilepsy, autism and anxiety disorders. Using molecular and behavioral approaches, we will determine the mechanisms and impact of aberrant DJ- 1/L-VDCC pathway in mediating anxiety-like disorders and epilepsy in two mouse models of TSC. These studies will lay down a biological framework to delineate underlying mechanisms that may be shared among comorbid neurological and neuropsychiatric diseases, paving a way for potential treatments for epilepsy, autism, anxiety disorders and TSC. Our investigations on DJ-1 and its downstream targets may also offer a pathway that can be exploited to expand our tools and avenues in treating complex, neurological disorders. Lastly, these studies will develop and sustain research excellence of a new investigator at NC A&T State University, a Historically Black College and University, catalyze institutional research culture, and enrich the university’s research environment. Importantly, our proposed investigations will provide underserved graduate and undergraduate students in biomedical sciences with robust research opportunities, contributing to the development of a diverse scientific workforce.

项目总结/摘要 癫痫、自闭症谱系障碍和焦虑症是高度共病的。实际上，海训方案就是这种情况。 尽管这个问题很重要，但这些疾病之间的分子联系很差 明白重要的是，缺乏可以减轻这些共病症状的药物治疗。 由于这些医疗需求，我们正在利用TSC作为一个模型系统，以获得更好的 了解癫痫、自闭症和焦虑症之间的联系机制。哺乳动物/机械 雷帕霉素靶蛋白（mTOR）在癫痫、孤独症、焦虑症和TSC中过度活跃。的激酶 调节蛋白质合成，我们以前的工作已经证明，mTOR的扰动极大地影响了 神经突触中的蛋白质水平，神经突触是介导神经元之间通讯的关键亚细胞结构。 值得注意的是，这些共病疾病表现为突触功能障碍。此外，我们发现mTOR 同样诱导和抑制突触蛋白水平。因此，慢性、过度活跃的mTOR可能会永久地保持 疾病状态下的突触导致一些蛋白质过度表达而另一些蛋白质表达不足。 与当mTOR过度活跃时过度表达的蛋白质不同，低表达的蛋白质的身份是不确定的。 蛋白质以及它们的水平是如何调节的相对未知。深入了解 当mTOR过度活跃时，蛋白质表达减少对于更好地理解 这些共病疾病是如何在分子上联系起来的我们最近发现mTOR控制着 突触DJ-1，一种新发现的RNA结合蛋白，抑制其相关mRNA的翻译。 因此，DJ-1可能介导当mTOR活跃时突触处或附近的蛋白质的低表达。两 这些低表达的蛋白质，其mRNA与DJ-1相关的是CaV1.2和α 2 δ 2-L型 电压依赖性钙通道（L-VDCC）亚基与癫痫、孤独症和焦虑症有关。 使用分子和行为方法，我们将确定异常DJ的机制和影响， 1/L-VDCC通路在两种TSC小鼠模型中介导焦虑样疾病和癫痫。这些 研究将建立一个生物学框架，以描述可能在以下方面共享的潜在机制： 共病的神经和神经精神疾病，为癫痫的潜在治疗铺平了道路， 自闭症焦虑症和TSC我们对DJ-1及其下游目标的研究也可能提供一个 可以利用这一途径来扩展我们治疗复杂神经系统疾病的工具和途径。 最后，这些研究将发展和维持一个新的研究人员在NC A&T国家卓越的研究 大学，一个历史上的黑人学院和大学，催化机构的研究文化，并丰富 大学的研究环境。重要的是，我们提出的调查将提供服务不足的毕业生 和本科生在生物医学科学与强大的研究机会，有助于 发展多元化的科学人才队伍。