SRF/MYOCD: new targets in Alzheimer's neurovasculature

描述(申请人提供)：阿尔茨海默病(AD)是一种多因素的神经退行性疾病。根据盛行的淀粉样级联假说，阿尔茨海默病的认知功能下降和明显的致病特征与淀粉样β-肽(A？)异常积聚有关。在大脑里。同时正在努力提高A？清除，防止其形成，还是发展抗-A？小分子，最近的证据表明，神经血管功能障碍和脑血流量受损(CBF)参与了AD的发病机制。基于我们第一阶段应用的已发表数据和本文提供的新的初步数据，我们试图从药物上削弱两种转录因子，血清反应因子(SRF)和肌钙蛋白(MYOCD)在AD患者脑血管平滑肌细胞(VSMC)中增强的活性。SRF/MYOCD构成了VSMC收缩基因程序的一个有效的转录开关，该基因在AD-VSMC中被夸大，并与导致AD小鼠模型中CBF减少的过度收缩表型一致。此外，新的初步数据支持SRF/MYOCD在A缺陷？VSMC清除与A？通过循环消除。综上所述，这些数据导致我们提出以下假设：AD VSMC中SRF/MYOCD活性升高导致小脑动脉的过度收缩表型和A？在A中，哪些因素导致CBF减少和神经血管解偶联？而特异性阻断MYOCD与SRF相互作用的药物将“解锁”过度收缩/A？AD VSMC表型，改善脑血流量，缓解痴呆症状。为验证这一假说而设计的具体目标包括：(1)通过文库筛选验证我们已确定的SRF/MYOCD的新的小分子抑制剂；(2)评估先导化合物对VSMC超收缩性和A？体外清除；(3)评估先导化合物使VSMC超收缩力正常化的能力，A？我们最近开发的一种新的AD表型小鼠模型的清除和行为缺陷。这些创新和高度稳健的研究有望发现一类新的潜在AD治疗药物，这些药物应该为进一步的毒性和临床前试验做好准备，从而为它们在正常化与AD和痴呆相关的脑血管调节障碍和神经血管解偶联方面的评估提供动力。目前，还没有有效的疗法来预防或逆转阿尔茨海默病(AD)及其相关痴呆的不可阻挡的病程。在这种神经退行性疾病中，一个共同的线索是流向大脑的血液流量的妥协。这项申请旨在评估一种潜在的新疗法类别，旨在破坏AD患者脑血管中显示的两种过度活跃的蛋白质。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder. According to the prevailing amyloid cascade hypothesis, cognitive decline and distinct pathogenic features in AD relate to abnormal accumulation of amyloid beta-peptide (A?) in the brain. While efforts are underway to enhance A? clearance, prevent its formation, or to develop anti- A? small molecules, recent evidence implicates neurovascular dysfunction and compromised cerebral blood flow (CBF) in the pathogenesis of AD. Based on published data derived from our Phase I application and novel preliminary data provided herein, we seek to pharmacologically undermine enhanced activity of two transcription factors, serum response factor (SRF) and myocardin (MYOCD), in cerebral vascular smooth muscle cells (VSMC) derived from patients with AD. SRF/MYOCD constitute a potent transcriptional switch for a VSMC contractile gene program, which is exaggerated in AD-VSMC and coincides with a hypercontractile phenotype leading to reduced CBF in mouse models of AD. Moreover, new preliminary data support SRF/MYOCD in defective A? clearance by VSMC and the expression of LRP1, which is a major mediator of A? elimination via the circulation. Together, these data lead us to formulate the following hypothesis: elevated SRF/MYOCD activity in AD VSMC leads to a hypercontractile phenotype in small cerebral arteries and the accumulation of A? which contribute to CBF reductions and neurovascular uncoupling as seen in A?, whereas drugs which specifically block MYOCD interaction with SRF will "unlock" the hypercontractile/ A? AD VSMC phenotype, improve CBF and alleviate symptoms of dementia. The specific aims designed to test this hypothesis include (1) validating novel small molecule inhibitors of SRF/MYOCD we have identified through library screening; (2) evaluating lead compounds for their ability to normalize VSMC hypercontractility and A? clearance in vitro; and (3) evaluating lead compounds for their ability to normalize VSMC hypercontractility, A? clearance, and behavioral deficits in a novel mouse model of AD phenotype we have recently developed. These innovative and highly robust studies are expected to uncover a new class of potential AD therapeutics that should be poised well for further toxicity and preclinical trials, thus providing impetus for their assessment in normalizing the cerebrovascular dysregulation and neurovascular uncoupling associated with AD and dementia. Currently, there are no effective therapies to prevent or reverse the inexorable course of Alzheimer's disease (AD) and associated dementias. A common thread amongst such neurodegenerative diseases is a compromise in blood flow to the brain. This application seeks to evaluate a potential new class of therapeutics designed to disrupt two proteins shown to be hyperactive in blood vessels of the brain of AD patients.