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High Throughput screen to identify "first of their kind" activators of ADCY10

高通量筛选，鉴定 ADCY10 的“同类首个”激活剂

基本信息

批准号：
10066301
负责人：
JOCHEN BUCK
金额：
$ 56.94万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066301
关键词：
Adenylate Cyclase Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Anions Autophagocytosis Autophagolysosome Bicarbonates Biochemical Biological Biological Assay Biological Models Brain Diseases Carbon Dioxide Cathepsins Cell Nucleus Cell membrane Cell model Cell physiology Cells Clinical Trials Complement Complex Cyclic AMP Data Defect Dementia Disease Environment Epidemic Equilibrium Exhibits Family Genetic Heterotrimeric GTP-Binding Proteins Hormones Human In Vitro Knock-out Laboratories Lipids Liquid substance Lumen of the Lysosome Lysosomes Mammalian Cell Methodology Microglia Mitochondrial Matrix Mitotic Modeling Molecular Structure Mus Nature Neurodegenerative Disorders Neurons Organelles Orthologous Gene Palliative Care Parkinson Disease Pathologic Pathology Pathway interactions Patients Permeability Pharmacology Phase Physiological Polysaccharides Process Proteins Regulation Research Second Messenger Systems Services Signal Transduction Source Symptoms System Testing Therapeutic age related neurodegeneration aged alkalinity base carbonate dehydratase disease-causing mutation high throughput screening improved inhibitor/antagonist misfolded protein novel strategies presenilin-1 protein aggregation protein degradation sensor small molecule therapeutically effective tool treatment strategy

项目摘要

Aberrant accumulation of protein aggregates is a common feature of age-related neurodegenerative diseases, including Alzheimer's disease. Cells clear aggregated material via autophagy. Lysosomes, the acidic organelles where proteins and unused cellular components are degraded and recycled, are the terminal compartment of autophagy. Long-lived, post-mitotic cells such as neurons are dependent upon continuous lysosomal turnover of cellular materials delivered by autophagy. With aging, lysosomes become less acidic, and their proteolytic activity decreases. In a cellular model of Alzheimer's disease, re-acidification of lysosomal pH increases autophagic flux and rescues cell function. We discovered a signaling cascade which regulates lysosomal acidification. Soluble adenylyl cyclase (sAC) is a source of the ubiquitous second messenger cAMP which is molecularly, structurally, biochemically, and functionally distinct from the family of plasma membrane-bound, hormone-regulated transmembrane forms of adenylyl cyclase. We showed sAC-generated cAMP promotes lysosomal acidification, and in the absence of sAC activity, autophagic flux is slowed. There are no pharmacological activators of sAC. We previously used high throughput screening to identify the most widely used pharmacological inhibitors specific sAC. We now propose to use high throughput screening and our battery of in vitro and cellular sAC assays to identify and characterize “first-of-their kind” small molecule activators selective for sAC usable in cellular systems. We hypothesize that sAC activators will facilitate lysosomal acidification and increase degradation of accumulated protein aggregates in cellular models of neurodegenerative disorders. These studies have the potential to supply proof- of-principle for a therapeutic strategy to treat neurodegenerative disorders.

蛋白质聚集体的异常积累是年龄相关的一个共同特征，神经退行性疾病，包括阿尔茨海默病。细胞通过以下途径清除聚集的物质：自噬溶酶体，酸性细胞器，蛋白质和未使用的细胞成分被降解和回收，是自噬的终末区室。长寿命，有丝分裂后细胞如神经元依赖于细胞物质的连续溶酶体更新通过自噬传递。随着年龄的增长，溶酶体的酸性降低，减少。在阿尔茨海默病的细胞模型中，溶酶体pH的再酸化增加自噬通量和拯救细胞功能。我们发现了一种信号级联，溶酶体酸化可溶性腺苷酸环化酶（sAC）是一种来源，普遍存在的第二信使cAMP在分子、结构、生物化学和功能上不同于质膜结合的、腺苷酸调节的跨膜形式的腺苷酸家族环化酶我们发现sAC产生的cAMP促进了溶酶体酸化，在没有cAMP的情况下， sAC活性降低，自噬通量减慢。没有sAC的药理学激活剂。我们以前使用高通量筛选来鉴定最广泛使用的药理学抑制剂特异性sAC。我们现在建议使用高通量筛选和我们的电池，体外和细胞sAC测定，以鉴定和表征“同类第一”小分子可用于蜂窝系统的sAC选择性活化剂。我们假设sAC激活剂促进溶酶体酸化并增加累积的蛋白质聚集体的降解，神经退行性疾病的细胞模型。这些研究有可能提供证据- 用于治疗神经退行性疾病的治疗策略的原则。