Huntington's Disease and Neurogenesis

描述（由申请人提供）：亨廷顿氏病（HD）是一种遗传性神经退行性疾病，可引起舞蹈徐动症、痴呆和精神病，在美国约有30，000人患病。HD的一种潜在治疗策略涉及通过刺激内源性神经元前体的增殖及其向受损脑区域的迁移来替换受损或死亡的神经元。在HD患者脑中邻近尾状核的脑室下区（SVZ）中观察到表达细胞增殖和未成熟神经元标记物的细胞数量增加。鉴于这一发现，并且因为生长因子在某些情况下具有神经保护作用并且还可以刺激神经发生，我们已经用皮下成纤维细胞生长因子-2（FGF-2）处理HD转基因R6/2小鼠，并且发现FGF-2使野生型小鼠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约30%，在HD转基因R6/2小鼠中约为150%。FGF-2还诱导新神经元从SVZ募集到HD转基因R6/2小鼠的新纹状体和大脑皮质中。在纹状体中，这些新的神经元是DARPP-32表达细胞，具有中等多刺神经元和苍白球投射的特性，与HD中丢失的神经元的表型一致。FGF-2还减少了聚谷氨酰胺聚集体，改善了运动性能，并延长了约20%的寿命。 我们假设FGF-2和其他生长因子可以刺激SVZ中的新神经元增殖，转运到纹状体和皮质，发展成熟神经元的功能特性，并整合到脑回路中以帮助抵消HD相关的缺陷。我们还假设，HD的功能结局将通过给予神经发生促进因子得到改善。我们将用以下具体目的来检验这些假设：（1）确定在转基因小鼠中扩增的突变型人Htt的表达影响用FGF-2处理的成年SVZ中的神经元前体细胞的方式。(2)在含FGF-2的成年R6/2 HD转基因小鼠中建立新生神经元的迁移目的地和功能命运。(3)检查FGF-2诱导的神经发生在改善转基因HD表型中的作用。(4)确定其他促进神经发生的生长因子，或FGF-2与其他生长因子的组合，是否比单独使用FGF-2更大程度地改善R6/2 HD转基因小鼠的表型和存活率。我们正在开发一种潜在的治疗方法，以保护神经元或取代亨廷顿病中的神经元。

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.