Identification of Novel Loci Interacting with the Kallmann Syndrome Gene Kal-1

与卡尔曼综合征基因 Kal-1 相互作用的新位点的鉴定

基本信息

批准号：
8513379
负责人：
Carlos Antonio Diaz-Balzac
金额：
$ 4.22万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513379
关键词：
Accounting Advisory Committees Affect Anosmia Area Axon Behavioral Assay Biological Assay Biomedical Research Caenorhabditis elegans Candidate Disease Gene Cell Adhesion Molecules Cells Chromosomes Code Complement Country Defect Development Diagnosis Disease Doctor of Philosophy Extracellular Matrix FGF8 gene FGFR1 gene Female Foundations Genes Genetic Genetic Complementation Test Genetic Epistasis Genomics Goals Hereditary Disease Human Hypogonadism Individual Infertility Inherited Kallmann Syndrome Klinefelter&apos s Syndrome Knowledge Label Mediating Medical Medicine Molecular Mutate Mutation Nervous system structure Neurons Neurosciences Research Pathway interactions Patient Care Pattern Phenotype Physicians Preparation Process RNA RNA Interference Reporter Research Role Scientist Single Nucleotide Polymorphism Map Site Smell Perception Specificity Students Technology Tissues Training Transgenic Organisms Translational Research base career college fundamental research gain of function genome sequencing hyposmia knock-down male migration mutant nervous system development novel programs promoter protein function public health relevance research and development research study

项目摘要

DESCRIPTION (provided by applicant): Kallmann Syndrome is a hereditary condition characterized by anosmia (the inability to smell) and hypogonadotropic hypogonadism resulting in infertility. This disorder affects 1 in 10,000 males and 1 in 40,000 females, but may be under diagnosed due to mild cases of hypogonadism or hyposmia. To date, five genes associated with KS have been identified, namely, KAL1, FGFR1, FGF8, PROKR2, and PROK2; though these only account for approximately 30% of all KS cases. The goal of this project is to identify and characterize novel genes that genetically interact with kal-1, a gene that codes for a cell adhesion protein of the extracellular matrix. We propose to accomplish this using a modifier screen of a kal-1 gain of function axon branching phenotype in C. elegans. A pilot screen of this phenotype has been used successfully by our group to identify several novel loci that genetically interact with KAL-1, both in worms and humans. The newly isolated mutations will be molecularly identified through single nucleotide polymorphism mapping and whole genome sequencing approaches. RNAi mediated knock down experiments and transgenic rescue experiments will be performed to further corroborate the identity of the mutation. The identified genes will then be molecularly and genetically characterized by three complementary approaches to gain a deeper understanding of how kal-1 acts in concert with these genes on the development of the nervous system and the role of the extracellular matrix in this process. First, I will perform a detailed neuroanatomical and phenotypic analysis of the modifier mutants with a focus on the nervous system. Second, their site of expression and the sub cellular localization will be determined, which will give important clues to the function of the protein. Third, double mutant and epistasis analyses will be performed in order to place the new mutations within a known genetic context. In the end, as more genes that interact with KAL-1 are identified, we will have a better understanding of their function and how their disruption in humans results in Kallmann Syndrome.

描述（由申请人提供）：卡尔曼综合症是一种遗传性疾病，其特征是嗅觉丧失（无法闻到气味）和促性腺素功能减退症，导致不育。这种疾病影响万分之一的男性和四万分之一的女性，但可能由于轻度性腺功能减退或嗅觉减退而未能得到诊断。迄今为止，已鉴定出 5 个与 KS 相关的基因，即 KAL1、FGFR1、FGF8、PROKR2 和 PROK2；尽管这些仅占所有 KS 病例的大约 30%。该项目的目标是识别和表征与 kal-1（编码细胞外基质细胞粘附蛋白的基因）发生遗传相互作用的新基因。我们建议使用线虫中功能轴突分支表型的 kal-1 增益的修饰筛选来实现这一点。我们的小组已成功地使用这种表型的试点筛选来鉴定在线虫和人类中与 KAL-1 基因相互作用的几个新位点。新分离的突变将通过单核苷酸多态性作图和全基因组测序方法进行分子鉴定。将进行RNAi介导的敲低实验和转基因拯救实验以进一步证实突变的身份。然后，将通过三种互补的方法对所鉴定的基因进行分子和遗传学表征，以更深入地了解 kal-1 如何与这些基因协同作用，影响神经系统的发育以及细胞外基质在此过程中的作用。首先，我将对修饰突变体进行详细的神经解剖学和表型分析，重点关注神经系统。其次，将确定它们的表达位点和亚细胞定位，这将为蛋白质的功能提供重要线索。第三，将进行双突变和上位分析，以便将新突变置于已知的遗传背景中。最后，随着更多与 KAL-1 相互作用的基因被识别，我们将更好地了解它们的功能以及它们对人类的破坏如何导致卡尔曼综合症。