Identification of Oligodendrocyte Stimulators

描述（由申请方提供）：少突胶质细胞（OL）是中枢神经系统的髓鞘形成细胞，在白色物质形成中起关键作用。严重的临床病症在早期发育期间影响中枢神经系统白色物质。这些情况包括脑室周围白色物质损伤（PWMI），影响了20%的极低出生体重早产儿。PWMI是由于前少突胶质细胞（PreOL）的损失，前少突胶质细胞是发育成髓鞘化OL的增殖细胞。 目前，我们不知道特异性靶向PreOL的药理学方法，导致这些细胞增殖增加。由于白色物质损伤是早产儿神经系统损伤的主要原因，因此开发PWMI的新治疗方法将具有重大的临床影响。 在该SBIR的第1阶段，我们建议使用高通量筛选来鉴定刺激PreOL增殖的化合物（“命中”）。这些研究被证明是非常成功的，因为我们鉴定了二氮嗪作为PreOL增殖的刺激剂，并且我们观察到该化合物在PWMI的鼠模型中促进髓鞘形成。二氮嗪通过激活KATP通道起作用，我们能够证明KATP通道组分在PreOL中的表达。我们还发现其他KATP激活剂刺激PreOL增殖。因此，我们实现了第一阶段提案的主要目标。 在II期研究中，我们建议将二氮嗪的研究扩展到临床前、概念验证研究（涉及细胞培养和动物研究）。我们将：（1）定义OL期对二氮嗪的特异性反应。(2)在动物模型中评价对PWMI的保护作用。(3)评估新生儿二氮嗪治疗的长期效果。 这项工作的长期目标是开发新的治疗药物，用于治疗早产儿的白色物质损伤。通过SBIR计划，NIH的支持将有助于加强耶鲁大学（Riverland博士）和JS Genetics（纽黑文，CT）科学家之间建立的富有成效的学术/工业合作，以发现新药。最终，像这样的研究将导致具有重大公共卫生效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白色损伤的早产儿出生和住院每年数以万计。 公共卫生相关性：本研究的目的是评估二氮嗪作为治疗早产儿白色物质损伤的治疗药物的效用。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名早产儿的白色损伤。

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.