SRF/MYOCD: new targets in Alzheimer's neurovasculature

描述（由申请人提供）：阿尔茨海默病（AD）是一种多因素神经退行性疾病。根据流行的淀粉样蛋白级联假说，AD的认知能力下降和独特的致病特征与淀粉样蛋白β肽（A？）在大脑里。虽然正在努力加强A？清除，防止其形成，或发展抗A？小分子，最近的证据表明神经血管功能障碍和受损的脑血流量（CBF）在AD的发病机制。基于来自我们的I期申请的已发表数据和本文提供的新的初步数据，我们试图在来自AD患者的脑血管平滑肌细胞（VSMC）中破坏两种转录因子，血清反应因子（SRF）和心肌素（MYOCD）的增强活性。SRF/MYOCD构成VSMC收缩基因程序的有效转录开关，其在AD-VSMC中被夸大，并且与导致AD小鼠模型中CBF减少的高收缩表型一致。此外，新的初步数据支持SRF/MYOCD在缺陷A？清除VSMC和LRP 1的表达，这是一个主要的介质A？通过循环消除。总之，这些数据使我们制定了以下假设：升高SRF/MYOCD活动在AD VSMC导致高收缩表型的小脑动脉和积累的A？这有助于CBF减少和神经血管解偶联，如A？所示，而特异性阻断MYOCD与SRF相互作用的药物将“解锁”高收缩/ A？AD VSMC表型，改善CBF，缓解痴呆症状。旨在验证这一假设的具体目标包括：（1）验证新的小分子抑制剂的SRF/MYOCD，我们已经确定通过图书馆筛选;（2）评估其正常化VSMC过度收缩和A？清除体外;和（3）评价他们的能力正常化VSMC过度收缩，A？清除，和行为缺陷的一种新的小鼠模型的AD表型，我们最近开发的。这些创新和高度稳健的研究预计将发现一类新的潜在AD治疗药物，这些药物应准备好进行进一步的毒性和临床前试验，从而为其评估正常化与AD和痴呆相关的脑血管失调和神经血管解偶联提供动力。目前，还没有有效的治疗方法来预防或逆转阿尔茨海默病（AD）和相关痴呆症的无情进程。这种神经退行性疾病的一个共同点是血液流向大脑的妥协。该申请旨在评估一种潜在的新型治疗剂，其设计用于破坏两种在AD患者脑血管中表现出过度活跃的蛋白质。

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.