MOLECULAR BASIS OF DARIERS DISEASE
DARIERS 病的分子基础
基本信息
- 批准号:2080913
- 负责人:
- 金额:$ 26.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-07-17 至 1996-05-31
- 项目状态:已结题
- 来源:
- 关键词:artificial skin athymic mouse cell adhesion molecules family genetics gene mutation genetic disorder human subject intercellular connection keratin keratinocyte keratosis follicularis linkage mapping molecular pathology protein structure function retinoids skin transplantation southern blotting tissue /cell culture ultraviolet radiation
项目摘要
Darier's disease (DD) is an autosomal doniinant genetic disorder
resulting in a disordered abnormally keratinizing epidermis. The
research plan is to identify the basic defect in DD by emphasizing
gene linkage analysis and studies of DD keratinocytes transplanted
to nude mice or cultured in skin equivalents. The avaflability of
several large pedigrees, candidate genes and other genetic probes
enhance the likelihood of the success of such an approach. The
disease is particularly intriguing since it has hyperkeratosis
suggesting abnormalities of intracellular maturation and clefting
and cell separation suggesting cell surface or cell membrane related
abnormalities. The role of environmental factors such as mechanical
trauma and sunlight in precipitating the disorder suggest thit the
disordered molecular may not be a known structural component of the
epidemiis and that a gene exclusion approach to define the primary
defect should be pursued.
Detailed Aims include: 1) Identification of the gene(s) whose
mutation(s) are responsible for DD. Using DNA from members of
several large already-identified kindreds with DD and we will assess
linkage of the DD gene to candidate genes selected on the basis of
the clinical and histologic characteristics of the epidermal
abnormalities. Should we find only data excluding these genes, we
will embark on a genome-wide search for the DD gene using probes
recognizing polymorphic loci throughout the genome for genetic
linkage and then physical techniques necessary to "close in" on the
DD gene. 2) Determination of the number of independent DD mutations
to ascertain whether there are more than one DD locus. Determining
the range of DD gene mutations, will enable assessment of
structure-function relationships better the normal gene product and
the DD product(s). 3) Proving that the basic pathophysiological
defect in DD resides in the epidemiis by transplantation studies in
nude mice and skin equivalents. Determination of the
pathophysiological defects in the behavior of keratinocytes cultured
from DD patients to address why phenotypic abnormalities are of late
onset and subject to environmental influence such as seasonal
changes and ultraviolet B sensitivity. Defining DD on both the
genetic and physiological levels will yield new understanding of the
defects which should lead to new therapeutic modalities for treating
DD.
Darier病(DD)是一种常染色体遗传性疾病
导致异常角化的表皮紊乱。这个
研究计划是通过强调以下方面来确定DD的基本缺陷
DD角质形成细胞移植的基因连锁分析及研究
裸鼠或在皮肤等效物中培养。的可用性
几个大的家系、候选基因和其他遗传探针
提高这种方法取得成功的可能性。这个
疾病特别耐人寻味,因为它有过度角化。
提示细胞内成熟和分裂异常
和细胞分离提示细胞表面或细胞膜相关
异常现象。机械等环境因素的作用
引发这种疾病的创伤和阳光表明
无序分子可能不是已知的结构成分
流行病学和一种基因排除的方法来定义初级
应追查缺陷。
具体目标包括:1)鉴定其基因(S)
突变(S)是引起DD的原因。使用来自成员的DNA
几个已经确定的大家族患有DD,我们将评估
DD基因与根据以下条件选择的候选基因的连锁
表皮的临床和组织学特征
异常现象。如果我们只找到排除这些基因的数据,我们
将开始使用探针在全基因组范围内搜索DD基因
识别基因组中的多态基因座
连接,然后是必要的物理技术,以“接近”
DD基因。2)确定独立DD突变的数量
以确定是否存在一个以上的DD基因座。确定
DD基因突变的范围,将使评估
结构-功能关系比正常的基因产物和
DD产品(S)。3)证明基本的病理生理
DD的缺陷存在于#年移植研究的流行病学中
裸鼠和皮肤替代品。确定了
角质形成细胞培养过程中的病理生理缺陷
从DD患者那里解决为什么表型异常是最近的
发病和受环境影响,如季节性
变化和对紫外线B的敏感性。在以下两个上定义DD
遗传和生理水平将产生新的理解
应导致新的治疗方式的缺陷
DD.
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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LOWELL Alan GOLDSMITH其他文献
LOWELL Alan GOLDSMITH的其他文献
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{{ truncateString('LOWELL Alan GOLDSMITH', 18)}}的其他基金
GORDON RESEARCH CONFERENCE ON EPITHELIAL DIFFERENTIATION
戈登上皮分化研究会议
- 批准号:
3433722 - 财政年份:1987
- 资助金额:
$ 26.24万 - 项目类别:
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Standard Grant