Huntington's Disease and Neurogenesis

描述(申请人提供)：亨廷顿病(HD)是一种遗传性神经退行性疾病，会导致舞蹈症、痴呆症和精神病，在美国约有30,000人受到影响。HD的一种潜在的治疗策略包括通过刺激内源性神经元前体的增殖和它们迁移到受损的脑区来替换受损或死亡的神经元。HD患者脑室下区(SVZ)尾状核附近可见大量表达细胞增殖和未成熟神经元标志的细胞。鉴于这一发现，以及由于生长因子在某些环境中具有神经保护作用，并且还可以刺激神经再生，我们用皮肤下成纤维细胞生长因子-2(FGF-2)处理HD转基因R6/2小鼠，发现在野生型小鼠和HD转基因R6/2小鼠中，FGF-2使SVZ中溴脱氧尿苷(BrdU)标记的双皮质素(DCX)表达细胞的数量增加了约30%，而在HD转基因R6/2小鼠中增加了约150%。在HD转基因R6/2小鼠中，成纤维细胞生长因子-2还诱导新的神经元从SVZ向新纹状体和大脑皮层募集。在纹状体，这些新的神经元是表达DARPP-32的细胞，具有中等刺状神经元和苍白球状突起的特性，与HD中丢失的神经元的表型一致。成纤维细胞生长因子-2还减少了聚谷氨酰胺聚集，改善了运动能力，并延长了约20%的寿命。 我们假设，成纤维细胞生长因子-2和其他生长因子可以刺激SVZ中的新神经元增殖，进入纹状体和皮质，发展成熟神经元的功能特性，并整合到大脑回路中，帮助弥补HD相关的缺陷。我们还假设HD患者的功能结局将通过应用促进神经发生的因子而得到改善。我们将以以下具体目标来检验这些假说：(1)确定在转基因小鼠中扩增的突变型人Htt的表达如何影响成体SVZ中接受成纤维细胞生长因子-2处理的神经前体细胞。(2)建立成年R6/2HD转基因小鼠新生神经元的迁移方向和功能去向。(3)检测成纤维细胞生长因子-2诱导的神经再生在改善转基因HD表型中的作用。(4)确定其他促进神经发生的生长因子，或与其他生长因子联合使用，是否能在更大程度上改善R6/2 HD转基因小鼠的表型和存活。我们正在开发一种潜在的治疗方法，以保护或取代亨廷顿病的神经元。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a hereditary neurodegenerative disorder that produces choreoathetosis, dementia and psychosis and affects about 30,000 individuals in the United States. One potential treatment strategy for HD involves the replacement of injured or dead neurons by stimulating the proliferation of endogenous neuronal precursors and their migration into damaged brain regions. An increase in the number of cells that express cell-proliferation and immature neuronal markers has been observed in the subventricular zone (SVZ) adjacent to the caudate nucleus in brains of patients with HD. Given this finding, and because growth factors are neuroprotective in some settings and can also stimulate neurogenesis, we have treated HD transgenic R6/2 mice with subcutaneous fibroblast growth factor-2 (FGF-2), and found that FGF-2 increased the number of bromodeoxyuridine (BrdU)-labeled, doublecortin (DCX)-expressing cells in the SVZ by ~30% in wild-type mice, and by ~150% in HD transgenic R6/2 mice. FGF-2 also induced recruitment of new neurons from the SVZ into the neostriatum and cerebral cortex of HD transgenic R6/2 mice. In the striatum, these new neurons were DARPP-32-expressing cells with properties of medium spiny neurons and pallidal projections, consistent with the phenotype of neurons lost in HD. FGF-2 also reduced polyglutamine aggregates, improved motor performance, and extended lifespan by ~20%. We hypothesize that FGF-2, and perhaps other growth factors, can stimulate new neurons in the SVZ to proliferate, transit into striatum and cortex, develop functional properties of mature neurons, and integrate into brain circuitry to help offset HD-related deficits. We also hypothesize that functional outcome in HD will be improved by administration of neurogenesis-promoting factors. We will test these hypotheses with the following Specific Aims: (1) Determine the manner in which expression of expanded mutant human Htt in transgenic mice affects neuronal precursor cells in the adult SVZ with FGF-2 treatment. (2) Establish the migratory destinations and functional fate of newborn neurons in adult R6/2 HD-transgenic mice with FGF-2. (3) Examine the role of FGF-2-induced neurogenesis in ameliorating the transgenic HD phenotype. (4) Determine if other neurogenesis-promoting growth factors, or FGF-2 combined with other growth factors, improve the phenotype and survival of R6/2 HD transgenic mice to a greater extent than FGF-2 alone.We are developing a potential therapy to protect neurons or replace them in Huntington's disease.