Identification of Oligodendrocyte Stimulators

描述(申请人提供)：少突胶质细胞(OL)是中枢神经系统的髓鞘细胞，在白质形成中起着关键作用。严重的临床疾病会在发育早期影响中枢神经系统的白质。这些情况包括脑室周围白质损伤(PWMI)，它影响高达20%的极低出生体重早产儿。PWMI是由于前少突胶质细胞(PreOdendrocell，PreOLs)的丧失，这些前少突胶质细胞是发育成髓鞘OL的增殖细胞。目前，我们还不知道有专门针对前OOL的药理学方法，从而导致这些细胞的增殖增加。由于白质损伤是早产儿神经系统损伤的主要原因，开发新的PWMI治疗方法将对临床产生重大影响。在这项SBIR的第一阶段，我们建议使用高通量筛选来鉴定能够刺激Preol增殖的化合物(HITS)。这些研究被证明是非常成功的，因为我们发现二氮嗪是Preol增殖的刺激因素，我们观察到这种化合物促进了PWMI小鼠模型的髓鞘形成。二氮嗪通过激活KATP通道起作用，我们能够证明KATP通道成分在PreOL中的表达。我们还发现，其他KATP激动剂可以刺激Preol的增殖。因此，我们实现了第一阶段提案的主要目标。在第二阶段研究中，我们建议将我们对二氮卓的研究扩展到临床前、概念验证研究中，包括细胞培养和动物研究。我们将：(1)确定二氮嗪对OL期的特异性反应。(2)在动物模型上评价对PWMI的保护作用。(3)评估新生儿二氮嗪治疗的远期疗效。这项工作的长期目标是开发治疗早产儿脑白质损伤的新型治疗剂。NIH通过SBIR计划提供的支持将有助于加强耶鲁大学(Rivkees博士)和JS Genetics(康涅狄格州纽黑文)的科学家为发现新药而建立的富有成效的学术/行业合作。最终，这样的研究将带来具有重大公共健康利益和商业价值的重要发现。我们还预计，这些研究将导致开发新的方法来治疗和预防每年出生和住院的数万早产儿的脑白质损伤。 公共卫生相关性：这项工作的目标是评估二氮卓作为治疗早产儿脑白质损伤的治疗剂的有效性。我们预计，这些研究将导致开发新的方法来治疗和预防每年出生和住院的数万早产儿的脑白质损伤。

DESCRIPTION (provided by applicant): Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation. Serious clinical disorders affect central nervous system white matter during early development. These conditions include periventricular white matter injury (PWMI), which affects up to 20% of very low birth weight premature infants. PWMI is due to loss of Pre- oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs. Presently, we are unaware of pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells. Because white matter injury is the leading cause of nervous system injury in premature infants, developing new treatments for PWMI will have a major clinical impact. Under Phase 1 of this SBIR, we proposed to use high-throughput screening to identify compounds ("hits") that would stimulate PreOL proliferation. These studies proved to be highly successful, as we identified diazoxide as a stimulator of PreOL proliferation, and we observed that this compound promotes myelination in a murine model of PWMI. Diazoxide acts by activating KATP channels, and we were able to demonstrate KATP channel component expression in PreOLs. We also found that other KATP activators stimulate PreOL proliferation. Thus, we achieved the major goal of our Phase 1 proposal. In Phase II studies, we propose to extend our study of diazoxide in preclinical, proof-of-concept studies involving cell culture and animal studies. We will: (1) Define OL-stage specific responses to diazoxide. (2) Evaluate protection against PWMI in animal models. (3) Assess long-term effects of neonatal diazoxide therapy. The long-term goal of this work is to develop novel therapeutic agents for the treatment of white matter injuries in premature infants. Support from the NIH through the SBIR program will serve to strengthen the productive academic/industrial collaboration established between scientists at Yale University (Dr. Rivkees) and JS Genetics (New Haven, CT) to discover novel drugs. Ultimately, research such as this will lead to important discoveries with significant public health benefit and commercial value. We also anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year. PUBLIC HEALTH RELEVANCE: The goal of this work is to assess the utility of diazoxide as a therapeutic agent for the treatment of white matter injuries in premature infants. We anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year.