Rational strategies for neuronal production and maturation from human cells.

人类细胞神经元产生和成熟的合理策略。

• 批准号: MR/L021129/1
• 负责人: Anna Philpott
• 金额: $ 82.53万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL021129%2F1
• 关键词: Rational; strategies; neuronal; production; maturation

Recent exciting finding have shown that normal cells from the skin (fibroblasts) can be converted directly to nerve cells by the addition of only 3 or 4 new specific proteins including so-called "proneural factors". This has opened up a wealth of possibilities for using these neurons to study nerve defects in conditions such as Parkinsons outside the body, and as a platform to test drugs that may enhance neural cell function. Moreover, findings in this area may ultimately underpin developments of methods to produce nerve cells to transplant back into patients with diverse neurological deficits. However, for these nerve cells to be used to model disease in a petri dish, or indeed as a supply to replace nerve cells lost in neurological disease, we need to be able to generate lots of mature nerve cells from fibroblasts that come straight from patients (as opposed to fibroblasts that have been chosen specifically for their ability to grow well in the lab). In addition, we need a way to direct the fibroblasts to form the correct type of nerve cell (e.g. cortical neurons for Stroke, dopaminergic nerve cells for Parkinsons disease, motor neurons for spinal cord injury or motor neuron disease). We are using our knowledge of the regulation of the proteins, and specifically a hyperactive protein that we think will drive much better maturation of these nerves as it does in the developing embryo, to create more effective protocols for making mature nerve cells from patient samples. We will see whether nerve cells generated in this way from patient fibroblasts look and behave the same as nerves produced from different patient-derived cells that have been produced in another way, via a stage that converts them to a "naive" form usually found in the early embryo (so called induced pluripotent cells). If we can use our hyperactive protein to enhance generation of mature nerves of specific types, we will then look at the genes turned on in these nerves to further explore why our neuronal differentiation factor is hyperactive.

最近令人兴奋的发现表明，来自皮肤的正常细胞（成纤维细胞）可以通过添加3或4种新的特定蛋白质（包括所谓的“前神经因子”）直接转化为神经细胞。这为利用这些神经元研究体外帕金森等疾病中的神经缺陷提供了丰富的可能性，并为测试可能增强神经细胞功能的药物提供了一个平台。此外，这一领域的发现可能最终会支持产生神经细胞的方法的发展，以移植回各种神经缺陷的患者。然而，为了将这些神经细胞用于培养皿中的疾病模型，或者作为替代神经系统疾病中失去的神经细胞的供应，我们需要能够从直接来自患者的成纤维细胞中产生大量成熟的神经细胞（与在实验室中专门选择的具有良好生长能力的成纤维细胞相反）。此外，我们需要一种方法来引导成纤维细胞形成正确类型的神经细胞（例如，中风的皮质神经元，帕金森病的多巴胺能神经细胞，脊髓损伤或运动神经元疾病的运动神经元）。我们正在利用我们对蛋白质调控的知识，特别是一种我们认为会促使这些神经更好地成熟的过度活跃的蛋白质，就像在发育中的胚胎中一样，来创造更有效的方案，从患者样本中制造成熟的神经细胞。我们将看到以这种方式从患者成纤维细胞中产生的神经细胞是否与以另一种方式产生的不同患者来源的细胞产生的神经细胞外观和行为相同，通过将它们转化为通常在早期胚胎中发现的“原始”形式（即所谓的诱导多能细胞）的阶段。如果我们能够利用这种过度活跃的蛋白质来促进特定类型的成熟神经的产生，那么我们就可以研究这些神经中开启的基因，从而进一步探索为什么我们的神经元分化因子是过度活跃的。

项目成果

Subcellular localisation modulates ubiquitylation and degradation of Ascl1.

• DOI: 10.1038/s41598-018-23056-4
• 发表时间: 2018-03-15
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Gillotin S;Davies JD;Philpott A
• 通讯作者: Philpott A

Multi-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiation.

• DOI: 10.1016/j.devcel.2017.04.004
• 发表时间: 2017-05-08
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Azzarelli R;Hurley C;Sznurkowska MK;Rulands S;Hardwick L;Gamper I;Ali F;McCracken L;Hindley C;McDuff F;Nestorowa S;Kemp R;Jones K;Göttgens B;Huch M;Evan G;Simons BD;Winton D;Philpott A
• 通讯作者: Philpott A

Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.

• DOI: 10.1158/1541-7786.mcr-20-0693
• 发表时间: 2020-12
• 期刊: Molecular cancer research : MCR
• 作者: Ali FR;Marcos D;Chernukhin I;Woods LM;Parkinson LM;Wylie LA;Papkovskaia TD;Davies JD;Carroll JS;Philpott A
• 通讯作者: Philpott A

Neurogenin3 phosphorylation controls reprogramming efficiency of pancreatic ductal organoids into endocrine cells.

• DOI: 10.1038/s41598-018-33838-5
• 发表时间: 2018-10-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Azzarelli R;Rulands S;Nestorowa S;Davies J;Campinoti S;Gillotin S;Bonfanti P;Göttgens B;Huch M;Simons B;Philpott A
• 通讯作者: Philpott A

The developmental origin of brain tumours: a cellular and molecular framework.

• DOI: 10.1242/dev.162693
• 发表时间: 2018-05-14
• 期刊: Development (Cambridge, England)
• 作者: Azzarelli R;Simons BD;Philpott A
• 通讯作者: Philpott A