BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES

碳酸酐酶（carbonic anhydrase，CA）及其相关蛋白（carbonic anhydrase-related protein，CA-RP）在呼吸、骨吸收、肾脏酸化、新生血管形成、信号转导、脑脊液和胃酸形成等多种生理过程中发挥重要作用。最近发现的CA IX和CA XII与肿瘤发生有关，并且在某些癌症中过度表达。这项研究的广泛目标是研究这个基因家族的功能基因组学，以确定个体成员对健康和疾病的重要性。我们有五个具体目标：1。 CA II缺乏症的生化和分子遗传学特征的完整研究。CA II缺乏是导致骨硬化症、肾小管性酸中毒和脑钙化的人类先天性代谢缺陷的基础，也提出了在CA II缺乏小鼠上的新研究。2. 表征CA II和CA IV双重缺陷的小鼠，并确定肾脏中的其他CA补偿CA IV缺陷。CA IV是肾脏和肠道上皮细胞以及毛细血管内皮细胞表面上的GPI锚定的膜CA。CA IV敲除小鼠缺乏预期的肾缺陷。3.表征CA VA基因敲除小鼠、新发现的CA Vb和CA V缺陷的候选者。CA VA是线粒体CA，被认为参与胚胎发育和尿素生成。4.描述CA IX的特征并确定其在细胞增殖调节和肿瘤发生中的作用。CA IX是一种肿瘤相关的CA，在几种癌症中过表达，在正常胃中表达。5.对CA XII的性质和功能基因组学进行表征。CA XII是一种新发现的跨膜CA，在几种癌症中过表达，并在正常肾脏和肠道中表达。这些研究应该增强我们对这些个体碳酸酐酶如何促进正常生理学的理解，单个CA缺陷如何产生疾病，以及为什么新发现的CA IX和XII在某些癌症中过度表达，并且还应该提出同工酶特异性CA抑制剂的新靶点。

The twelve known carbonic anhydrases (CAs) and CA-related proteins (CA- RPs) play important roles in diverse physiological processes including respiration, bone resorption, renal acidification, gluconeogenesis, signal transduction, and formation of cerebrospinal fluid and gastric acid. The recently discovered CA IX and CA XII are related to oncogenesis and are over-expressed in certain cancers. The broad goal of this research is to study the functional genomics of this gene family to determine the importance of individual members to health and disease. We have five specific aims: 1. Complete studies characterizing the biochemical and molecular genetics of CA II deficiency. CA II deficiency is the basis for the human inborn error of metabolism producing osteopetrosis, renal tubular acidosis, and brain calcification, novel studies are also proposed on the CA II-deficient mouse. 2. Characterize the mouse doubly deficient for CA II and CA IV and determine what other CA in kidney compensates for CA IV deficiency. CA IV is the GPI-anchored membrane CA on surfaces of epithelial cells in kidney and gut and of capillary endothelial cells. The CA IV null mouse lacks the expected renal defect. 3. Characterize the CA VA gene knockout mouse, the newly discovered CA Vb, and candidates for CA V deficiency. CA VA is the mitochondrial CA thought to be involved in gluconeogenesis and ureagenesis. 4. Characterize CA IX and define its role in the regulation of cell proliferation and in oncogenesis. CA IX is a tumor-associated CA that is over-expressed in several cancers and expressed in normal stomach. 5. Characterize the properties and the functional genomics of CA XII. CA XII is a newly discovered, transmembrane CA that is over-expressed in several cancers and expressed in normal kidney and intestine. These studies should enhance our understanding of how thee individual carbonic anyhydrases contribute to normal physiology, how single CA deficiencies produce disease, and why the newly discovered CAs IX and XII are over-expressed in certain cancers, and should also suggest new targets for isozyme-specific CA inhibitors.