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Exploiting the hair-brain connection to treat perinatal brain disease

利用头发与大脑的联系来治疗围产期脑部疾病

基本信息

批准号：
8173388
负责人：
SAMUEL JEREMY PLEASURE
金额：
$ 30.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8173388
关键词：
Ablation Accounting Address Affect Animals Antibodies Area Biological Models Biology Birth Blood Blood - brain barrier anatomy Brain Brain Diseases Cell Transplantation Cell Transplants Cells Cessation of life Child Critiques Data Development Diffuse Disease Dorsal Embryo Erinaceidae Evaluation Event Face Fostering Funding Funding Opportunities Genetic Goals Hair Hair follicle structure Head Hippocampus (Brain)Human Hypoxia Hypoxic Brain Damage Individual Inflammation Injury Institutes Ischemic-Hypoxic Encephalopathy Lesion Ligands Metabolic Diseases Methodology Mission Morbidity - disease rate Mus Mutant Strains Mice Neurologic Neurons Newborn Infant Oligodendroglia Other Genetics Oxygen Pathway interactions Perinatal Phenotype Pilot Projects Probability Proteins Reagent Reporter Research Risk Role Route Scalp structure Science Signal Transduction Skin Solutions Staging Structure Study Section Syndrome Testing Therapeutic Therapeutic Agents Transgenic Organisms United States National Institutes of Health Update Writing base dentate gyrus design enzyme deficiency extracellular gene therapy innovation insight interest meetings migration mind control mortality mutant nerve stem cell novel novel therapeutic intervention overexpression postnatal progenitor small molecule therapeutic target therapy development

项目摘要

DESCRIPTION (provided by applicant): We've developed extensive preliminary data showing that Sonic Hedgehog (Shh), produced by the hair follicles dorsal to the cortex, diffuses from the cells of origin to act within the brain to regulate the development of the hippocampal dentate gyrus and the migration of oligodendrocyte progenitors within the cortex at late embryonic and early postnatal stages. Using antibodies to extracellular Shh we are able to show that the amount of Shh reaching the developing cortex is reduced in mice with conditional ablation of Shh in the hair follicles and skin and that there is reduced signaling in transgenic signaling reporter mice in the brain. This indicates that the functional amounts of ligand reaching the cortex are reduced in these mice. These studies suggest the possibility that other protein ligands, if produced in the skin and hair follicles at high enough levels, would have access to the later embryonic and early postnatal developing brain, allowing us to circumvent some of the hurdles inherent in gene therapy or cell transplantation targeted to the cortex. In this proposal I will test this hypothesis and begin to lay the groundwork for determining the viability of this approach in humans. There are several difficult to treat disorders manifesting themselves around birth that may ultimately be amenable to this route of treatment. One particularly important syndrome is perinatal hypoxic-ischemic brain injury. Newborns with this syndrome have decreased oxygen supply due to events surrounding traumatic birth leading to significant injury including death of immature neurons and glial precursors. Recent studies have identified promising parenteral therapies in animals that are moving into human trials, but these face the possibility of causing increased off-target effects and morbidities because of the need to give these protein based agents intravenously. If they could be delivered locally and diffuse from the hair follicles and this might allow more targeted treatment with reduced morbidity. In addition, there are a host of genetic metabolic diseases that present with catastrophic consequences soon after birth due to enzyme deficiencies or other genetic lesions. Thus, I have developed this proposal to test the prospects for this approach.

描述（由申请人提供）：我们已经开发了大量的初步数据，表明由皮质背侧毛囊产生的 Sonic Hedgehog (Shh) 从起源细胞扩散到大脑内发挥作用，调节胚胎晚期和出生后早期皮质内海马齿状回的发育和少突胶质细胞祖细胞的迁移。使用细胞外Shh抗体，我们能够证明，在毛囊和皮肤中条件性消除Shh的小鼠中，到达发育中皮质的Shh数量减少，并且转基因信号报告小鼠大脑中的信号传导减少。这表明这些小鼠中到达皮质的配体的功能量减少了。这些研究表明，如果皮肤和毛囊中产生足够高的水平，其他蛋白质配体就有可能进入胚胎后期和产后早期发育的大脑，从而使我们能够绕过针对皮质的基因治疗或细胞移植中固有的一些障碍。在这个提案中，我将测试这个假设，并开始为确定这种方法在人类中的可行性奠定基础。有几种难以治疗的疾病在出生时表现出来，最终可能适合这种治疗途径。一种特别重要的综合征是围产期缺氧缺血性脑损伤。患有这种综合征的新生儿由于创伤性出生事件导致氧气供应减少，导致严重损伤，包括未成熟神经元和神经胶质前体的死亡。最近的研究已经在动物身上发现了有希望的肠外疗法，这些疗法正在进入人体试验，但由于需要静脉注射这些基于蛋白质的药物，这些疗法可能会导致脱靶效应和发病率增加。如果它们可以局部输送并从毛囊扩散，这可能会允许更有针对性的治疗并降低发病率。此外，还有许多遗传代谢疾病，由于酶缺乏或其他遗传病变，在出生后不久就会带来灾难性后果。因此，我提出了这个建议来测试这种方法的前景。