Enhanced Neural Stem Cell Production in the Aging Brain

增强衰老大脑中神经干细胞的产生

• 批准号: 6790163
• 负责人: Madhusudan Viswanath Peshwa
• 金额: $ 13.68万
• 依托单位: NEOCYTEX BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790163
• 关键词: aging; animal old age; apoptosis; cell differentiation; cell growth regulation; cell population study; cell proliferation; dicarboxylate; drug adverse effect; drug screening /evaluation; fibroblasts; geriatrics; glia; human tissue; laboratory rat; mesenchyme; nerve stem cell; nervous system regeneration; neural degeneration; neurogenesis; neurons; pluripotent stem cells; pyrimidine analog

DESCRIPTION (provided by applicant): NewNeural, Inc. is proposing to develop a small molecule drug (MS-818) that will significantly boost the production of new brain cells in patients who have suffered debilitating loss of brain cells and brain cell function. Our long-term strategy is to develop cell replacement therapies for patients with diseases such as stroke, Alzheimer's disease, Parkinson's disease, and age-associated memory impairment-- where loss of brain cells is associated with disease progression. We previously reported that transplanted neural stem cells display extensive migration and positional incorporation in the 24-month old rat brains, and those memory-impaired rats had significant improvement in cognitive function four weeks after transplantation. Recently, we discovered that the heterocyclic pyfimidine compound MS-818, when injected into aged rats (27 months old), induced the proliferation of neural stem cells by 7-fold. The compound also increased the proliferation of human neural stem cells in culture. Our hypothesis, supported in part by preliminary observations, is that MS-818 directly induces the proliferation of endogenous neural stem cells, which can then migrate to and repopulate the disease-affected regions of the brain. If this hypothesis is proven correct, MS-818 will offer a powerful new approach for treating patients with neurodegenerative conditions where the accelerated production of new neural cells may help improve cognitive and other neural functions. Our objective in this Phase I proposal is to confirm the feasibility of using MS-818 to promote dose-dependent neurogenesis in cell culture and animal models. We plan to test our hypothesis and accomplish our objectives with the following three specific aims: Aim 1. Confirm that MS-818 enhances neurogenesis by specifically inducing the proliferation of human NSCs in culture. Aim 2. Confirm that the MS-818-treated human neural stem cells are able to multiply and differentiate into neurons and glial cells and Aim 3. Demonstrate that MS-818 can enhance neurogenesis in aged rats in a dose-dependent manner. In Phase II, our objective will be to evaluate pharmacological effects of MS-818 on cognitive functions in animal models of disease. The extent and duration of functional improvement will be monitored and quantified, and pharmacokinetics and toxicity studies will be conducted in animals. Upon the completion of these studies, we expect to generate data to support further investigational new drug (IND)-enabling studies in animal models, in preparation for human clinical trials.

描述（由申请人提供）：NewNeural, Inc.提议开发一种小分子药物（MS-818），该药物将显著促进脑细胞和脑细胞功能衰弱性丧失患者新脑细胞的产生。我们的长期战略是为患有中风、阿尔茨海默病、帕金森病和与年龄相关的记忆障碍等疾病的患者开发细胞替代疗法，这些疾病的脑细胞损失与疾病进展有关。我们之前报道过，移植的神经干细胞在24个月大的大鼠大脑中表现出广泛的迁移和位置整合，并且那些记忆受损的大鼠在移植后四周的认知功能有显著改善。最近，我们发现将杂环嘧啶化合物MS-818注射到老年大鼠（27个月大）体内，可诱导神经干细胞增殖7倍。该化合物还能促进培养的人类神经干细胞的增殖。我们的假设部分得到了初步观察的支持，即MS-818直接诱导内源性神经干细胞的增殖，然后这些细胞可以迁移到并重新填充受疾病影响的大脑区域。如果这一假设被证明是正确的，MS-818将为治疗神经退行性疾病患者提供一种强有力的新方法，在这种疾病中，加速新神经细胞的产生可能有助于改善认知和其他神经功能。我们在这个I期项目中的目标是确认在细胞培养和动物模型中使用MS-818促进剂量依赖性神经发生的可行性。我们计划通过以下三个具体目标来检验我们的假设并实现我们的目标：目标1。证实MS-818通过特异性诱导培养的人NSCs增殖来促进神经发生。目标2。证实ms -818处理的人类神经干细胞能够增殖并分化为神经元、神经胶质细胞和Aim 3。证明MS-818能以剂量依赖的方式促进老年大鼠神经发生。在II期，我们的目标是评估MS-818对疾病动物模型认知功能的药理作用。将监测和量化功能改善的程度和持续时间，并在动物中进行药代动力学和毒性研究。在完成这些研究后，我们期望产生数据来支持进一步的动物模型研究性新药（IND）研究，为人体临床试验做准备。