Regulation of Neural Stem Cells and Neurogenesis by Autophagy Genes

自噬基因对神经干细胞和神经发生的调节

基本信息

批准号：
10673701
负责人：
JUN-LIN GUAN
金额：
$ 37.15万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673701
关键词：
Ablation Adult Affect Aging Alzheimer&apos s Disease Animals Autophagocytosis Biochemical Biological Brain C-terminal Cell Maintenance Cell model Cell physiology Cells Complex Cytoplasm Data Defect Development Disease Disease Progression Dominant-Negative Mutation Family Functional disorder Funding Future Generations Genes Genetic Goals Growth Homeostasis Huntington Disease Hydrogen Peroxide Hypoxia In Vitro Injury Knock-in Knock-in Mouse Knockout Mice Laboratories Maintenance Metabolic Modeling Molecular Mus Mutagenesis Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organ Oxidative Stress PTK2 gene Parkinson Disease Phosphorylation Play Process Proteins Regulation Risk Factors Role TBK1 gene age related aged cell age conditional knockout design effective therapy gain of function in vivo insight juvenile animal mouse model nerve stem cell neurogenesis neuromechanism neuroregulation prevent receptor response stem cells synergism

项目摘要

In adult brains, neural progenitor/stem cells (NSCs) are responsible for the generation of new neurons for the maintenance of the existing circuitry and after injuries. Deficiency in NSC maintenance and/or neurogenesis contributes to both developmental defects and neurodegenerative diseases for which aging is a major risk factor. The long-term goal of the proposed studies is to determine the molecular and cellular mechanisms of NSC regulation in both young and aged animals, which can lead to the development of effective therapies for neurodegenerative diseases. Autophagy is a highly conserved cellular process for degradation of bulk cytoplasmic materials for maintenance of cellular homeostasis, and dysfunctions in autophagy have been implicated in various diseases, including neurodegeneration and other age-related disorders. FIP200 (FAK-family Interacting Protein of 200 kDa) was initially identified in our laboratory and subsequently shown as one component of the ULK1/Atg13/FIP200 complex essential for the induction of autophagy. In the previous funding period, we found that, deletion of Fip200, but not other autophagy genes Atg5, Atg7 and Atg16L1, led to defective NSC maintenance and neurogenesis, suggesting a potential role for the non-canonical function of FIP200 in NSC regulation through controlling p62 aggregate formation. In additional prelim studies, we obtained rigorous genetic evidence that non-canonical function of FIP200 is required for NSC maintenance and neurogenesis by generation and analyses of another unique mouse model with FIP200-4A mutation in NSCs that blocks autophagy function of FIP200 specifically. Additionally, we found that the FIP200 C-terminal region (FIP200-CT) could interact with p62, consistent with recent studies showing its importance in degrading p62 aggregates. Moreover, we found that FIP200 can regulate TBK1 activation, which can phosphorylate p62 to regulate its degradation, and that FIP200 also interacts with the TBK1 adaptor, AZI2. In a second set of prelim studies, we analyzed the role of another autophagy gene Beclin1 in NSCs employing new Becn1 KI mice and found that increased autophagy protected NSC pool and their neurogenesis in aged Becn1 KI mice without affecting NSC in young mice. Lastly, we obtained additional prelim data suggesting that oxidative stress may synergize with autophagy-deficiency to promote p62 aggregate formation. Building upon these preliminary and prior studies, we propose to 1). investigate the mechanisms of non-canonical functions of FIP200 and potential synergy with its autophagy function in the regulation of NSCs, 2). analyze the role and mechanisms of enhanced autophagy to prevent NSC pool decline and promote neurogenesis in Becn1 KI mice, and 3). explore the role and mechanisms of NSC maintenance and neurogenesis in autophagy-deficiency mice after oxidative insult and during aging. Together, these studies will significantly advance our understanding of the regulation of NSC and neurogenesis by autophagy genes that may contribute to future design of effective therapies for neurodegenerative and other related diseases.

在成人大脑中，神经祖细胞/干细胞 (NSC) 负责新神经元的生成用于现有电路的维护和受伤后的维护。 NSC 维护不足和/或神经发生导致发育缺陷和神经退行性疾病衰老是一个主要的风险因素。拟议研究的长期目标是确定分子和细胞幼年和老年动物中 NSC 的调节机制，可导致神经退行性疾病的有效治疗方法。自噬是一种高度保守的细胞过程用于维持细胞稳态的大量细胞质材料的降解和功能障碍自噬与多种疾病有关，包括神经退行性疾病和其他与年龄相关的疾病失调。 FIP200（200 kDa 的 FAK 家族相互作用蛋白）最初是在我们的实验室中鉴定出来的，随后显示为 ULK1/Atg13/FIP200 复合物的一个组成部分，对于诱导自噬。在之前的资助期间，我们发现，Fip200被删除，但其他自噬基因没有被删除 Atg5、Atg7 和 Atg16L1 导致 NSC 维持和神经发生缺陷，这表明 FIP200 通过控制 p62 聚集体形成在 NSC 调节中的非规范功能。在通过额外的初步研究，我们获得了严格的遗传证据，表明 FIP200 的非典型功能是通过生成和分析另一种独特的小鼠模型来维持 NSC 维持和神经发生所需 NSC 中 FIP200-4A 突变可特异性阻断 FIP200 的自噬功能。此外，我们还发现 FIP200 C 末端区域 (FIP200-CT) 可以与 p62 相互作用，这与最近的研究一致它在降解 p62 聚集体中的重要性。此外，我们发现FIP200可以调节TBK1的激活，它可以磷酸化 p62 以调节其降解，并且 FIP200 还与 TBK1 接头相互作用， AZI2。在第二组初步研究中，我们分析了另一个自噬基因 Beclin1 在 NSC 中的作用使用新的 Becn1 KI 小鼠，发现自噬增加可以保护 NSC 库及其神经发生在老年 Becn1 KI 小鼠中，不影响年轻小鼠的 NSC。最后，我们获得了额外的初步数据表明氧化应激可能与自噬缺陷协同作用，促进 p62 聚集体的形成。基于这些初步和先前的研究，我们建议 1)。研究 FIP200 的非典型功能机制及其在 NSC 调节中与其自噬功能的潜在协同作用，2)。分析增强自噬预防NSC池衰退的作用及机制，促进 Becn1 KI 小鼠的神经发生，以及 3)。探讨 NSC 维持的作用和机制氧化损伤后和衰老过程中自噬缺陷小鼠的神经发生。这些研究共同将显着增进了我们对自噬基因对 NSC 和神经发生的调节的理解可能有助于未来设计针对神经退行性疾病和其他相关疾病的有效疗法。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Autophagy Blockade Limits HER2+ Breast Cancer Tumorigenesis by Perturbing HER2 Trafficking and Promoting Release Via Small Extracellular Vesicles.

自噬阻断通过扰乱 HER2 运输并促进小细胞外囊泡释放来限制 HER2 乳腺癌肿瘤发生。

DOI：
发表时间：
2021
期刊：
影响因子：
11.8
作者：
Hao, Mingang;Yeo, Syn Kok;Turner, Kevin;Harold, Alexis;Yang, Yongguang;Zhang, Xiaoting;Guan, Jun
通讯作者：
Guan, Jun

Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model.

通过突变敲入小鼠模型的生成和分析揭示了 FIP200 的自噬依赖性和非自噬依赖性功能的独特作用。

DOI：
发表时间：
2016-04-01
期刊：
影响因子：
10.5
作者：
Chen, Song;Wang, Chenran;Yeo, Syn;Liang, Chun;Okamoto, Takako;Sun, Shaogang;Wen, Jian;Guan, Jun
通讯作者：
Guan, Jun

Single-cell RNA-sequencing reveals distinct patterns of cell state heterogeneity in mouse models of breast cancer.

单细胞 RNA 测序揭示了乳腺癌小鼠模型中细胞状态异质性的独特模式。

DOI：
发表时间：
2020
期刊：
影响因子：
7.7
作者：
Yeo, Syn Kok;Zhu, Xiaoting;Okamoto, Takako;Hao, Mingang;Wang, Cailian;Lu, Peixin;Lu, Long Jason;Guan, Jun
通讯作者：
Guan, Jun

Autophagy Regulates Craniofacial Bone Acquisition.

自噬调节颅面骨的获取。