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ENAMEL MATRIX SERINE PROTEINASE 1

牙釉质基质丝氨酸蛋白酶 1

基本信息

批准号：
6707511
负责人：
JAMES P SIMMER
金额：
$ 21.69万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2007-02-28
项目状态：
已结题

项目摘要

Enamel matrix serine proteinase 1 (EMSP1) is proposed to process enamel proteins during the secretory stage, and degrade enamel proteins during the early maturation stage of amelogenesis. EMSP1 is believed to be critical for proper dental enamel formation and defects in the human EMSP1 gene are suspected of causing amelogenesis imperfecta. Two hypotheses are tested: l. EMSP1 function is essential for the correct processing of enamel matrix proteins during the secretory stage of enamel formation, and that a loss of function can result in hypoplastic enamel. 2. EMSP1 function is essential for the degradation of enamel matrix proteins during the transition/early maturation stages of enamel formation, and that a loss of function can result in hypommeralized enamel. The following 4 Specific.Aims are proposed to test these hypotheses: l. To determine the temporal and spatial expression of EMSP1 during the secretory. transition. and maturation stages of enamel biomineralization. In situ hybridization and immunohistochemistry will be performed on mouse maxillae and mandibles. The first and second molars and incisors will be analyzed from newborn, postnatal (PN) days 2, 4, 6, 8 and 14 and adult. 2. To characterize the enzymatic activity of EMSP1 on amelogenin. Recombinant pig amelogenin will be digested by recombinant pig EMSP1 in vitro. The digestion products will be characterized by Edman degradation and mass spectrometry and compared to amelogenin cleavage sites that occur in vivo. 3. To characterize enamel formation in the absence of mouse EMSP1 expression. EMSP1 knock-out mice will be generated and characterized. 4. To determine the genetic linkage of the human EMSP1 gene with inherited defects of dental enamel formation. In collaboration with 3 laboratories that have assembled large numbers of kindreds suffering for amelogenesis imperfecta (AI), a candidate gene approach will be used to establish linkage between the human EMSP1 gene and AI . Accomplishing these aims will gain important insights into the action of EMSP1 in the organization, processing, turnover, and degradation of enamel matrix proteins during enamel biomineralization.

釉基质丝氨酸蛋白酶1（EMSP 1）被认为在分泌期加工釉蛋白，在成釉的早期成熟阶段降解釉蛋白。EMSP 1被认为是正确的牙釉质形成的关键，人类EMSP 1基因的缺陷被怀疑会导致釉质形成障碍。两个假设进行了测试：l。EMSP 1功能对于在釉质形成的分泌阶段正确加工釉质基质蛋白是必不可少的，并且功能的丧失可导致釉质发育不全。2. EMSP 1功能对于釉质形成的过渡/早期成熟阶段期间釉质基质蛋白的降解是必不可少的，并且功能的丧失可导致低矿化釉质。提出了以下4个具体目标来检验这些假设：1.探讨EMSP 1在乳腺癌细胞分泌过程中的时空表达。过渡和釉质生物矿化的成熟阶段。将对小鼠上颌骨和下颌骨进行原位杂交和免疫组织化学。将从新生儿、出生后（PN）第2、4、6、8和14天以及成年分析第一和第二磨牙和切牙。2.研究EMSP 1对釉原蛋白的酶促活性。重组猪釉原蛋白将在体外被重组猪EMSP 1消化。消化产物将通过Edman降解和质谱法表征，并与体内发生的釉原蛋白切割位点进行比较。3.表征小鼠EMSP 1表达缺失时的釉质形成。将产生EMSP 1敲除小鼠并进行表征。4.目的探讨EMSP 1基因与遗传性牙釉质形成缺陷的遗传连锁关系。在与3个实验室的合作，已经组装了大量的患釉质发育障碍（AI）的激酶，候选基因的方法将被用来建立人类EMSP 1基因和AI之间的联系。实现这些目标将获得重要的洞察EMSP 1在组织，加工，营业额，并在釉质生物矿化过程中的釉质基质蛋白降解的行动。