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
基本信息
- 批准号:10120126
- 负责人:
- 金额:$ 38.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:5&apos-AMP-activated protein kinaseAdultAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAstrocytesBiologicalBiologyBlood - brain barrier anatomyBone Morphogenetic ProteinsBrainBrain DiseasesCaenorhabditis elegansCaloric RestrictionCardiovascular DiseasesCell SurvivalCellsClinical TrialsCognitionComputational BiologyCrystallographyDementiaDendritesDevelopmentDiabetes MellitusDiseaseDistantEnergy IntakeEngineeringFRAP1 geneFastingGenerationsGoalsGrantHereditary Spastic ParaplegiaHomeostasisHuntington DiseaseInheritedLeadLongevityMalignant NeoplasmsMalignant neoplasm of lungMemoryMetabolicMusNatural regenerationNeoplasm MetastasisNerve DegenerationNeurodegenerative DisordersNeuronsNeurosciencesNutrientObesityParalysedParentsPathologyPathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsProcessProductionProtein KinaseReceptor SignalingRegulationResearchScientistSignal TransductionSignaling ProteinStarvationSynapsesTherapeuticUnited StatesWorkage relatedbone morphogenetic protein receptor type Ibone morphogenetic protein receptorscancer cellcancer survivalcancer therapycognitive functiondesignimprovedinhibitor/antagonistmTOR inhibitionmouse modelnerve stem cellneurogenesisnovelnovel strategiesprotein expressionreceptorrelating to nervous systemresponsesenescencesmall moleculestem cell differentiationtargeted treatmenttau Proteinstraffickingtreatment strategytumor growth
项目摘要
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。mTOR的抑制和
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。放慢速度的能力
衰老过程是显著延迟神经变性疾病,癌症,
和心血管疾病。事实证明,限制热量摄入可以延长寿命并影响寿命
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加在一起,是独一无二的
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN LANGENFELD其他文献
JOHN LANGENFELD的其他文献
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{{ truncateString('JOHN LANGENFELD', 18)}}的其他基金
Targeting BMP type 2 receptor for the treatment of breast cancer.
靶向 BMP 2 型受体治疗乳腺癌。
- 批准号:
10515890 - 财政年份:2022
- 资助金额:
$ 38.92万 - 项目类别:
Developing bone morphogenetic receptor II inhibitors for the treatment of cancer
开发用于治疗癌症的骨形态发生受体 II 抑制剂
- 批准号:
10672554 - 财政年份:2018
- 资助金额:
$ 38.92万 - 项目类别:
Developing bone morphogenetic receptor II inhibitors for the treatment of cancer
开发用于治疗癌症的骨形态发生受体 II 抑制剂
- 批准号:
10405106 - 财政年份:2018
- 资助金额:
$ 38.92万 - 项目类别:
Developing bone morphogenetic receptor II inhibitors for the treatment of cancer
开发用于治疗癌症的骨形态发生受体 II 抑制剂
- 批准号:
9978003 - 财政年份:2018
- 资助金额:
$ 38.92万 - 项目类别:
THE ROLE OF A BONE MORPHOGENETIC PROTEIN IN LUNG CANCER
骨形态发生蛋白在肺癌中的作用
- 批准号:
6792062 - 财政年份:2002
- 资助金额:
$ 38.92万 - 项目类别:
THE ROLE OF A BONE MORPHOGENETIC PROTEIN IN LUNG CANCER
骨形态发生蛋白在肺癌中的作用
- 批准号:
6604004 - 财政年份:2002
- 资助金额:
$ 38.92万 - 项目类别:
THE ROLE OF A BONE MORPHOGENETIC PROTEIN IN LUNG CANCER
骨形态发生蛋白在肺癌中的作用
- 批准号:
6470841 - 财政年份:2002
- 资助金额:
$ 38.92万 - 项目类别:
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