Sitosterolemia

该基金的主要目的是确定谷甾醇血症的分子、生化和临床缺陷。在这种遗传性疾病中，纯合子表现为动脉粥样硬化加速伴主动脉瓣狭窄、致命性心肌梗死、肌腱和结节性黄瘤、溶血性发作伴红细胞变形和血小板减少以及致残性关节炎发作。 从化学上讲，植物甾醇（谷甾醇、豆甾醇、菜油甾醇和燕麦甾醇）及其各自的5 α-二氢衍生物（谷甾烷醇和菜油甾烷醇）和胆甾烷醇在除脑外的所有组织中积累，因为肠道吸收增强和肝脏清除减少。 此外，胆固醇生物合成在具有上调的LDL受体的单核细胞中不协调地下调，以产生增加的胆固醇和植物甾醇沉积物，使得细胞类似于致动脉粥样硬化泡沫细胞。主要研究目标是（1）定位并克隆已映射到2 p21、序列突变的负责高吸收的谷固醇血症基因，并通过突变产物允许植物固醇通过肠细胞不受限制地吸收和转运来阐明机制。 策略包括用一组密集的微卫星标记进行精细定位，以将异常基因区域缩小到约1cM，从可疑区域和相邻区域构建YAC重叠群和BAC重叠群。 对可能发生突变的区域的候选基因进行测序。 来自30个谷甾醇血症家族的40个受影响的纯合子的DNA已经组装。 (2)在3种大鼠模型中研究胆固醇和植物甾醇代谢，其中菜油甾醇和谷甾醇约占血浆甾醇的15%，与人类谷甾醇血症相似。 在这些模型中，我们建议测量谷甾醇和胆固醇吸收，评估胆固醇生物合成（在人类谷甾醇血症中被抑制），并评估长期胆固醇喂养对动脉粥样硬化、植物甾醇和胆固醇积累和代谢的影响。 (3)检查谷甾醇（24-乙基胆固醇）向胆酸和鹅去氧胆酸的转化，并确定其途径。 谷甾醇血症是一种罕见的疾病，但了解增强甾醇吸收和积累的机制将提供关键信息，制定更好的治疗动脉粥样硬化的一般人群。

The major aims of this grant are to define the molecular, biochemical, and clinical defects in sitosterolemia. In this recessively inherited disease, homozygotes show accelerated atherosclerosis with aortic stenosis, fatal myocardial infarctions, tendon and tuberous xanthomas, hemolytic episodes with deformed erythrocytes and thrombocytopenia, and attacks of disabling arthritis. Chemically, plant sterols (sitosterol, stigmasterol, campesterol, and avenosterol) and their respective 5alpha-dihydro derivatives (sitostanol and campestanol) and cholestanol accumulate in all tissues except brain because of enhanced intestinal absorption and reduced hepatic removal. In addition, cholesterol biosynthesis is discordantly down-regulated in monocytes with upregulated LDL receptors to produce increased cholesterol and plant sterol deposits such that the cells resemble atherogenic foam cells. Key research objectives are (1) locate and clone the sitosterolemia gene responsible for hyperabsorption that has been mapped to 2p21, sequence mutations, and elucidate the mechanism by with the mutated product permits unrestricted uptake and transport of plant sterols through the enterocyte. Strategies include fine mapping with a dense set of microsatilliate markers to narrow the abnormal gene region to approximately 1cM, construction of YAC contig and BAC contig with critical cDNAs from the suspected and adjoining regions. Sequence candidate genes from the region for possible mutations. DNA from 40 affected homozygotes from 30 sitosterolemic families have been assembled. (2) Investigate cholesterol and plant sterol metabolism in 3 rat models where campesterol and sitosterol constitute approximately 15 percent of the plasma sterols similar to human sitosterolemia. In these models, we propose to measure sitosterol and cholesterol absorption, assess cholesterol biosynthesis (inhibited in human sitosterolemia) and evaluate the effect of long term cholesterol feeding on development of atherosclerosis, plant sterol and cholesterol accumulation and metabolism. (3) Examine the conversion of sitosterol (24-ethyl cholesterol) to cholic acid and chenodeoxycholic acid and ascertain the pathway. Sitosterolemia is a rare disease but understanding the mechanism of enhanced sterol absorption and accumulation will provide key information to formulate better treatment of atherosclerosis in the general population.