Determining the effects of bone morphogenetic protein receptor 2 (BMPR2) inhibition on neural stem cell neurogenesis and regulation of energy homeostasis in Alzheimer’s disease and cancer

确定骨形态发生蛋白受体 2 (BMPR2) 抑制对阿尔茨海默病和癌症中神经干细胞神经发生和能量稳态调节的影响

• 批准号: 10120126
• 负责人: JOHN LANGENFELD
• 金额: $ 38.92万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-06 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10120126
• 关键词: 5' -AMP-activated protein kinase; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Astrocytes; Biological; Biology; Blood - brain barrier anatomy; Bone Morphogenetic Proteins; Brain; Brain Diseases; Caenorhabditis elegans; Caloric Restriction; Cardiovascular Diseases; Cell Survival; Cells; Clinical Trials; Cognition; Computational Biology; Crystallography; Dementia; Dendrites; Development; Diabetes Mellitus; Disease; Distant; Energy Intake; Engineering; FRAP1 gene; Fasting; Generations; Goals; Grant; Hereditary Spastic Paraplegia; Homeostasis; Huntington Disease; Inherited; Lead; Longevity; Malignant Neoplasms; Malignant neoplasm of lung; Memory; Metabolic; Mus; Natural regeneration; Neoplasm Metastasis; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Nutrient; Obesity; Paralysed; Parents; Pathology; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Process; Production; Protein Kinase; Receptor Signaling; Regulation; Research; Scientist; Signal Transduction; Signaling Protein; Starvation; Synapses; Therapeutic; United States; Work; age related; bone morphogenetic protein receptor type I; bone morphogenetic protein receptors; cancer cell; cancer survival; cancer therapy; cognitive function; design; improved; inhibitor/antagonist; mTOR inhibition; mouse model; nerve stem cell; neurogenesis; novel; novel strategies; protein expression; receptor; relating to nervous system; response; senescence; small molecule; stem cell differentiation; targeted treatment; tau Proteins; trafficking; treatment strategy; tumor growth

PROJECT SUMMARY Bone morphogenetic proteins (BMP) are highly expressed in lung cancer cells promoting survival and distant spread. Increased BMP expression also occurs in the brain with natural aging and is accelerated in Alzheimer’s disease (AD). BMP promotes the differentiation of adult neural stem cells (NSC) into astroglial cells and suppresses their differentiation into neurons, which are required for memory and cognition. Inhibition of the BMP receptors promotes the regeneration of new neurons and improves cognition in aging mice and mouse models of AD. In our parent R01, we are developing BMPR2 inhibitors for the treatment of lung cancer. We have developed significantly more specific BMPR2 inhibitors. We find that inhibition of BMPR2 causes potent inhibition of mechanistic target of rapamycin 1 (mTORC1), mTORC2, and Akt. Furthermore, these novel BMPR2 inhibitors cause the activation of AMP-activated protein kinase (AMPK). The inhibition of mTOR and the activation of AMPK have not only been shown to suppress tumor growth but this same regulatory signature has been shown to increase longevity and to decrease neurodegenerative diseases. Targeting BMPR2 represents a novel strategy to treat AD and other neurodegenerative diseases by promoting neurogenesis. Neurodegenerative diseases and cancer are diseases of aging. The ability to slow the aging process is a potential way to significantly delay the onset of neurodegenerative diseases, cancer, and cardiovascular disease. Limiting caloric intake has been shown to increase longevity and impact the development and treatment of age-related diseases including AD. The cellular response to caloric restriction (CR) is dependent on the activation of AMPK and suppression of mTOR signaling, which is the same regulatory signature induced by our BMPR2 inhibitors. A drug that can induce the biologic response mimicking CR could have a major impact on age-related diseases. We hypothesize that BMPR2 inhibition with small molecules can be used to treat neurodegenerative diseases and cancer, which involves the suppression of mTOR and the activation of AMPK. We have established a team of scientists with expertise in BMP biology, BMP receptor trafficking, neuroscience, medicinal chemistry, computational biology, neural pathology, and crystallography who together, are uniquely qualified to successfully complete the following specific aims. Aim 1: Determine in SAMP8 mouse models of Alzheimer’s disease, the effects of our new generation of BMPR2 inhibitors engineered to cross the blood-brain barrier on NSC neurogenesis, synaptic and dendritic integrity, and astrocyte senescence. Aim 2: Determine in C. elegans the regulation of AMPK and mTOR with BMPR2 during starvation. Examine whether AMPK and mTOR regulate daf-4(BMPR2) trafficking during starvation.

项目概要 骨形态发生蛋白（BMP）在肺癌细胞中高表达，促进生存和 随着自然衰老，BMP 的表达也会增加，并且会加速。 阿尔茨海默病 (AD) 促进成体神经干细胞 (NSC) 分化为星形胶质细胞。 细胞并抑制其分化为记忆和认知抑制所需的神经元。 BMP 受体的作用促进新神经元的再生并改善衰老小鼠的认知能力 AD小鼠模型。 在我们的母公司 R01 中，我们正在开发用于治疗肺癌的 BMPR2 抑制剂。 我们开发了更特异性的 BMPR2 抑制剂，我们发现抑制 BMPR2 会产生显着有效的效果。 抑制雷帕霉素 1 (mTORC1)、mTORC2 和 Akt 的机械靶标此外，这些小说。 BMPR2 抑制剂引起 AMP 激活蛋白激酶 (AMPK) 的激活，抑制 mTOR 和 AMPK 的激活不仅被证明可以抑制肿瘤生长，而且具有相同的调节特征 已被证明可以延长寿命并减少神经退行性疾病。 靶向 BMPR2 代表了一种治疗 AD 和其他神经退行性疾病的新策略 促进神经发生。神经退行性疾病和癌症是延缓衰老的疾病。 衰老过程是显着延缓神经退行性疾病、癌症、 和心血管疾病。限制热量摄入已被证明可以延长寿命并影响健康。 包括 AD 在内的与年龄相关的疾病的发生和治疗。细胞对热量限制的反应。 (CR) 依赖于 AMPK 的激活和 mTOR 信号传导的抑制，这与 我们的 BMPR2 抑制剂诱导的调节特征，一种可以诱导模仿生物反应的药物。 CR 可能对与年龄相关的疾病产生重大影响。 我们发现用小分子抑制 BMPR2 可用于治疗神经退行性疾病 疾病和癌症，其中涉及 mTOR 的抑制和 AMPK 的激活。 建立了一支由 BMP 生物学、BMP 受体贩运、神经科学、 药物化学、计算生物学、神经病理学和晶体学共同构成了独特的学科 有资格成功完成以下具体目标。 目标 1：确定我们新一代药物在阿尔茨海默病 SAMP8 小鼠模型中的作用 BMPR2 抑制剂被设计为穿过血脑屏障，影响 NSC 神经发生、突触和 树突完整性和星形胶质细胞衰老。 目标 2：确定秀丽隐杆线虫饥饿期间 AMPK 和 mTOR 与 BMPR2 的调节。 检查 AMPK 和 mTOR 是否调节饥饿期间的 daf-4(BMPR2) 运输。