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

项目摘要 骨形态发生蛋白（BMP）在肺癌细胞中高度表达，促进生存， 远距离传播BMP表达的增加也发生在自然衰老的大脑中，并且在衰老过程中加速。 阿尔茨海默病（AD）。BMP促进成体神经干细胞向星形胶质细胞分化 细胞并抑制它们分化为神经元，这是记忆和认知所必需的。抑制 BMP受体促进新神经元的再生，改善衰老小鼠的认知能力， AD小鼠模型。 在我们的母体R 01中，我们正在开发用于治疗肺癌的BMPR 2抑制剂。我们有 开发了更特异的BMPR 2抑制剂。我们发现BMPR 2的抑制会导致 抑制雷帕霉素1（mTORC 1）、mTORC 2和Akt机制靶点。此外，这些小说 BMPR 2抑制剂引起AMP活化蛋白激酶（AMPK）的活化。抑制mTOR和 AMPK激活不仅显示出抑制肿瘤生长，而且这种相同的调节信号 已被证明可以延长寿命并减少神经退行性疾病。 靶向BMPR 2代表了通过以下方式治疗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衰老的疾病。减缓的能力 衰老过程是显著延迟神经变性疾病，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在内的年龄相关疾病的发展和治疗。细胞对热量限制的反应 (CR)依赖于AMPK的激活和mTOR信号的抑制，这是相同的。 由我们的BMPR 2抑制剂诱导的调节信号。一种能引起类似于 CR可能对年龄相关疾病产生重大影响。 我们假设用小分子抑制BMPR 2可用于治疗神经退行性变 疾病和癌症，其中涉及mTOR的抑制和AMPK的激活。我们有 建立了一个科学家团队，在BMP生物学，BMP受体运输，神经科学， 药物化学、计算生物学、神经病理学和晶体学，他们共同研究了 有资格成功完成以下具体目标。 目的1：确定在阿尔茨海默病的SAMP 8小鼠模型中，我们的新一代的效果 BMPR 2抑制剂的工程改造，以跨越血脑屏障对NSC神经发生，突触和 树突完整性和星形胶质细胞衰老。 目的2：在C中测定。elegans在饥饿时用BMPR 2调节AMPK和mTOR。 检查AMPK和mTOR是否在饥饿期间调节daf-4（BMPR 2）运输。

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.