GENETIC STUDY OF PROTEIN C DEFICIENCY AND THROMBOSIS

蛋白质 C 缺乏和血栓形成的遗传学研究

• 批准号: 6115963
• 负责人: EDWIN G BOVILL
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6115963
• 关键词: Native Americans; clinical research; family genetics; gene expression; gene mutation; genetic disorder; human genetic material tag; human subject; linkage mapping; phenotype; protein C; protein deficiency; prothrombin; thrombosis

The objective of this project is to better understand the biosynthesis, activation, and functional properties of the vitamin K-dependent plasma proteins involved in blood clotting and the consequences of mutations in the proteins on hereditary thrombosis. This project specifically explores, through the study of protein C mutations, the fundamental mechanisms by which these proteins are modified, transported, and secreted prior to their involvement in Ca2+-membrane associated processes. Another direction of the project is the chromosomal localization and identification of a putative second gene, THROMC, that is associated with thrombotic disease in a large type I protein C deficient kindred of Native American decent. Specific aims are to identify new protein C mutations in families exhibiting thrombophilia; construct, express, and biochemically characterize secreted and non-secreted naturally occurring mutant forms of protein C; and determine by genetic linkage analysis the existence and location of a second gene (THROMC) associated with thrombosis. Family members are also phenotyped in regard to thrombotic disease and several clinical markers of the prothrombotic state, including protein C, prothrombin fragment 1.2, and fibrin D-dimer levels. Unrelated thrombophilic families with and without protein C deficiency are also examined for the association of THROMC with disease. During the reporting period 12/1/97 - 11/30/98, at the GCRC we obtained whole blood and plasma samples from 5 members of the protein C deficient kindred. Samples from 26 family members who live in other geographic locations were also obtained, but not at the GCRC. The total number of family members included in the study is now 328. We will continue using the GCRC to obtain blood samples from family members living near here throughout the study period.

该项目的目的是更好地了解参与血液凝固的维生素K依赖性血浆蛋白的生物合成、激活和功能特性，以及蛋白质突变对遗传性血栓形成的后果。 该项目通过蛋白C突变的研究，专门探讨了这些蛋白在参与Ca 2+膜相关过程之前被修饰、转运和分泌的基本机制。 该项目的另一个方向是染色体定位和鉴定一个推定的第二个基因，THROMC，这是与血栓性疾病在一个大的I型蛋白质C缺乏的美洲原住民体面的亲属。具体的目标是确定新的蛋白C突变的家庭表现出血栓形成;构建，表达和生化特性的分泌和非分泌的天然突变形式的蛋白C;并确定通过遗传连锁分析的存在和位置的第二个基因（THROMC）与血栓形成。 家族成员也被分型为血栓性疾病和血栓前状态的几种临床标志物，包括蛋白C、凝血酶原片段1.2和纤维蛋白D-二聚体水平。 无关的有或无蛋白C缺乏的血栓形成家族也检查了THROMC与疾病的关系。 在报告期间1997年12月1日至1998年11月30日，我们在GCRC获得了5名蛋白C缺乏亲属的全血和血浆样本。 还从居住在其他地理位置的26名家庭成员中获得了样本，但不在GCRC。 目前，参与研究的家庭成员总数为328人。 在整个研究期间，我们将继续使用GCRC从居住在附近的家庭成员那里获取血液样本。