Exploiting the hair-brain connection to treat perinatal brain disease

描述（由申请人提供）：我们已经开发了广泛的初步数据，表明由皮层背侧毛囊产生的Sonic Hedgehog （Shh）从起源细胞扩散到大脑内，在胚胎晚期和出生后早期调节海马齿状回的发育和皮层内少突胶质细胞祖细胞的迁移。利用细胞外Shh的抗体，我们能够证明到达发育中的皮层的Shh数量在毛囊和皮肤中有条件地消融的小鼠中减少了，并且在转基因信号报告小鼠中大脑中的信号也减少了。这表明，在这些小鼠中，到达皮质的配体的功能数量减少了。这些研究表明，如果在皮肤和毛囊中产生足够高水平的其他蛋白质配体，就有可能进入胚胎后期和出生后早期发育中的大脑，从而使我们能够绕过针对皮质的基因治疗或细胞移植所固有的一些障碍。在这个提议中，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。有一些难以治疗的疾病在出生时表现出来，最终可能适用于这种治疗途径。一个特别重要的综合征是围产期缺氧缺血性脑损伤。新生儿由于创伤性分娩导致严重损伤，包括未成熟神经元和神经胶质前体死亡，导致该综合征的氧气供应减少。最近的研究已经确定了有希望的动物外注射疗法，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，这些疗法面临着导致脱靶效应和发病率增加的可能性。如果它们可以局部传递并从毛囊扩散，这可能会使更有针对性的治疗降低发病率。此外，还有许多遗传代谢疾病，由于酶缺乏或其他遗传病变，在出生后不久就会出现灾难性的后果。因此，我提出了这个建议来测试这种方法的前景。

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.