Tooth pulp as a source for neuronal precursor cells to study neurogenetic disorde

牙髓作为神经元前体细胞的来源来研究神经遗传疾病

• 批准号: 8413042
• 负责人: LAWRENCE T REITER
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413042
• 关键词: 15q; Alleles; Angelman Syndrome; Animal Model; Autistic Disorder; Autopsy; Biological Models; Biopsy; Brain; Cell Line; Cells; Cephalic; Characteristics; Cicatrix; DNA; Dental Pulp; Dentistry; Disabled Children; Disease; Distress; Epigenetic Process; Fibroblasts; Fragile X Syndrome; Future; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Goals; Hereditary Disease; Human; Human Genetics; In Vitro; Ion Channel; Lead; Measures; Methods; Methylation; Modeling; Molecular; Mus; Neural Crest; Neural Crest Cell; Neurons; Pain; Pathogenesis; Patients; Pattern; Peripheral Nervous System; Physiological; Physiology; Property; Sampling; Skin; Source; Stem cells; Sum; Synapses; Syndrome; Testing; Therapeutic; Tissues; Tooth structure; Transcript; Transplantation; Viral Vector; autism spectrum disorder; autistic children; base; brain tissue; cell type; deciduous tooth; developmentally disabled; immunogenic; imprint; in vivo; insight; lymphoblast; mouse model; neurogenetics; neuron development; neurophysiology; novel strategies; precursor cell; protein expression; receptor; research study; stem

The study of neurogenetic disorders like Angelman, Rett and fragile X syndromes as well as autism spectrum disorders has depended largely on the analysis of gene/protein expression in non-neuronal biospecimens like lymphoblast and fibroblast cel lines. Although some analysis has been possible in post-mortem human brain tissue for neurogenetic syndromes, this tissue is often of variable quality and in limited amounts. Recently there has been an initiative to induce pluripotent stem cels (iPSCs) from patient fibroblasts and differentiate these iPSCs into various neuronal lineages. There are several problems with this approach: 1) fibroblasts must be obtained though a fairly invasive skin biopsy which leaves a scar and causes undue pain and distress in developmentally disabled or autistic children; 3) induction of fibroblasts into stem cells (reprogramming) and then into neuronal lineages is a laborious task that may not maintain epigenetic marks on the DNA that are essential to proper gene regulation in the native neuronal tissues; and 4) viral vectors which are themselves immunogenic are used to reprogram iPSCs limiting the downstream aplication of these neurons for therapeutic transplantations. Here we propose to use dental pulps from exfoliated primary teeth (EPT), as a source of stem cells for the study of a variety of neurogenetic syndromes. Dental pulp stem cells differentiate into functional neurons in vitro and in vivo. Dental pulps from EPT are also an easily obtainable source of cranial neural crest (CNC) cells. The majority of the cells in the peripheral nervous system, including neurons, are derived from the neural crest. Based on the extensive collaborative sum of our expertise in genetics, dental pulp stem cells and neurophysiology, we feel that this novel approach will provide a fresh perspective to the way we study expresion changes, epigenetics and neurophysiology in an ex-vivo model system for human neurogenetic disorders. !

Angelman、Rett和脆性X综合征等神经遗传性疾病的研究 自闭症谱系障碍在很大程度上依赖于对基因/蛋白质的分析 在淋巴母细胞和成纤维细胞等非神经性生物细胞系中的表达。 虽然在死后的人脑组织中已经可以进行一些分析 神经发生综合征，这种组织通常质量不同，数量有限。 最近，有一项关于从小鼠骨髓中诱导多能干细胞的研究 患者成纤维细胞，并将这些IPSCs分化为不同的神经元谱系。那里 这种方法有几个问题：1)成纤维细胞必须通过相当的 侵入性皮肤活检会在患者身上留下疤痕并造成不必要的疼痛和痛苦 发育障碍或自闭症儿童；3)成纤维细胞向干细胞的诱导 (重新编程)然后进入神经元谱系是一项费力的任务，可能不会 在DNA上保持表观遗传标记，这对正确的基因调控是必不可少的 天然神经组织；以及4)本身具有免疫原性的病毒载体 用来重新编程ipscs，限制这些神经元的下游应用 治疗性移植。在这里，我们建议使用去角质的牙髓 乳牙(EPT)作为干细胞的来源，用于研究多种神经发生 综合症。牙髓干细胞在体外和体外分化为功能神经元 活着。来自EPT的牙髓也是一种容易获得的脑神经脊线来源 (Cnc)单元。周围神经系统中的大多数细胞，包括 神经元，是从神经脊派生出来的。基于广泛的协作和 我们在遗传学、牙髓干细胞和神经生理学方面的专业知识，我们认为 新的方法将为我们研究表达的方式提供一个新的视角 人类体外模型系统中的变化、表观遗传学和神经生理学 神经遗传性疾病。 好了！

项目成果

Characterization of neurons from immortalized dental pulp stem cells for the study of neurogenetic disorders.

从永生化的牙髓干细胞中的神经元来研究神经遗传疾病。

• DOI: 10.1016/j.scr.2015.11.004
• 发表时间: 2015-11
• 期刊: Stem cell research
• 影响因子: 1.2
• 作者: Urraca N;Memon R;El-Iyachi I;Goorha S;Valdez C;Tran QT;Scroggs R;Miranda-Carboni GA;Donaldson M;Bridges D;Reiter LT
• 通讯作者: Reiter LT

Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons.

15Q重复的重大转录变化，但没有安吉尔曼综合征删除干细胞衍生的神经元。

• DOI: 10.1186/s13229-018-0191-y
• 发表时间: 2018
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Urraca N;Hope K;Victor AK;Belgard TG;Memon R;Goorha S;Valdez C;Tran QT;Sanchez S;Ramirez J;Donaldson M;Bridges D;Reiter LT
• 通讯作者: Reiter LT

A Rare Inherited 15q11.2-q13.1 Interstitial Duplication with Maternal Somatic Mosaicism, Renal Carcinoma, and Autism.

• DOI: 10.3389/fgene.2016.00205
• 发表时间: 2016
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Urraca N;Potter B;Hundley R;Pivnick EK;McVicar K;Thibert RL;Ledbetter C;Chamberlain R;Miravalle L;Sirois CL;Chamberlain S;Reiter LT
• 通讯作者: Reiter LT

Effects of hTERT immortalization on osteogenic and adipogenic differentiation of dental pulp stem cells.

• DOI: 10.1016/j.dib.2016.01.009
• 发表时间: 2016-03
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Ikbale el-A;Goorha S;Reiter LT;Miranda-Carboni GA
• 通讯作者: Miranda-Carboni GA

Culturing and Neuronal Differentiation of Human Dental Pulp Stem Cells.

• DOI: 10.1002/cphg.28
• 发表时间: 2017-01-11
• 期刊: Current protocols in human genetics
• 作者: Goorha S;Reiter LT
• 通讯作者: Reiter LT