BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES

已知的12种碳酸酐酶（CAs）及其相关蛋白（CA- RPs）在呼吸、骨吸收、肾酸化、糖异生、信号转导、脑脊液和胃酸的形成等多种生理过程中发挥重要作用。最近发现的caix和caxii与肿瘤发生有关，并在某些癌症中过度表达。本研究的主要目标是研究该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。钙II缺乏症的生化和分子遗传学的完整研究。CA II缺乏是人类先天性代谢错误产生骨质疏松、肾小管酸中毒和脑钙化的基础，对CA II缺乏小鼠也提出了新的研究。2. 表征小鼠CA II和CA IV双重缺陷，并确定肾脏中哪些其他CA补偿CA IV缺陷。caiv是肾、肠上皮细胞和毛细血管内皮细胞表面的gpi锚定膜CA。CA - IV缺失小鼠没有预期的肾缺损。3. 描述CA - VA基因敲除小鼠、新发现的CA - Vb和CA - V缺乏症候选者的特征。CA VA是线粒体CA，被认为参与糖异生和尿素发生。4. 描述caix的特征并确定其在细胞增殖和肿瘤发生中的调节作用。caix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. 鉴定caxii的特性和功能基因组学。CA XII是一种新发现的跨膜CA，在几种癌症中过表达，在正常肾和肠中表达。这些研究将增强我们对三种单独的碳酸酐酶如何促进正常生理，单一CA缺乏如何产生疾病，以及为什么新发现的CAs IX和XII在某些癌症中过度表达的理解，并且还应该为同工酶特异性CA抑制剂提供新的靶点。

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.