Molecular Pathophysiology of Human Growth Disorders
人类生长障碍的分子病理生理学
基本信息
- 批准号:6331833
- 负责人:
- 金额:$ 8.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-04-01 至 2002-06-30
- 项目状态:已结题
- 来源:
- 关键词:cell line family genetics gene deletion mutation gene expression genetic mapping growth hormone releasing hormone high performance liquid chromatography hormone receptor hormone regulation /control mechanism human genetic material tag pathologic process pituitary dwarfism postnatal growth disorder prenatal growth disorder restriction fragment length polymorphism somatotropin tissue /cell culture transfection
项目摘要
DESCRIPTION (adapted from the application)
We have undertaken a patient-based study of the role of molecular defects in
families and individuals with growth disorders that are likely to be due to
genetic aberrations in constituents of the Growth Hormone axis. Families and
individuals with growth disorders-isolated Growth Hormone (GH) deficiency or GH
excess, as well as multiple pituitary hormone deficiencies-are evaluated for
mutations in candidate genes chosen according to the specific endocrine
phenotype of that family/individual. The objective of this study is to
understand the mechanism by which mutations in genes result in abnormal growth.
The elucidation of the causes o abnormal growth-and the specific derangements
wrought by them-will allow a greater understanding of the physiology of
'normal' growth and shed light on the larger question of what proportion of
human attributes (e.g., height) are determined by genetics. The Principal
Investigator currently holds an NIDDK-funded Mentored Clinical Scientist
Development Award (K-08 DK02569) through June 30, 2002, and is requesting
additional funds to improve the ability to complete the goals as stated in this
and the original application.
We hypothesize that a subset of individuals with growth disorders have a
mutation in a gene within the Growth Hormone axis. After a detailed endocrine
evaluation, we evaluate families for mutations in PROP-1, PIT-1, LHX3, LHX4,
Growth Hormone Releasing Hormone (GHRH), the GHRH Receptor (GHRHR), the Growth
Hormone Secretagogue (GHS, or GHRELIN), the GHS receptor (GHSR) and Growth
Hormone (GH1). We analyze for genetic linkage/haplotype disequilibrium to
identify a candidate gene, then screen exon-by-exon, by either Denaturing
High-Performance Liquid Chromatography (DHPLC) or Single Strand Conformation
Polymorphism Analysis (SSCA) then directly sequence the conformationally unique
exon in affected and unaffected members of a family. We then confirm mutation
status with an automated Single Nucleotide Polymorphism (SNP) analyzer, or
alternatively, through the use of restriction fragment length polymorphism
(RFLP) analysis (including induced-mutagenesis, when necessary). The mutated
gene product is then transfected into an appropriate cell line (e.g., a
mammalian somatotrope or somatomammotrope) and expressed to determine the
resulting specific cellular derangement. As our previous work has shown, the
specific cell line used for expression is critical to obtaining physiologically
relevant results. Both genomic DNA and tumor cDNA are used as templates for
mutation analysis in tumor tissue, allowing for differentiation between
germ-line and somatic mutations. A novel aspect of this grant is the full
spectrum analysis of these subjects-proceeding from patient to hormones to DNA
to cell system. The transfection studies meant to complete the initial work has
been started and will be the major focus of the remaining two years of the K-08
grant period. The enhanced funding will increase throughput in all phases by
increasing personnel and equipment, improving the Principal Investigator's
prospects for obtaining an Individual Investigator Research Grant (R-01), and
his ultimate goal of becoming an independent investigator.
描述(改编自应用程序)
我们进行了一项以患者为基础的研究,探讨分子缺陷在
家庭和个人的生长障碍,可能是由于
生长激素轴成分的遗传畸变。家庭和
生长障碍个体-孤立性生长激素(GH)缺乏症或GH
过量,以及多种垂体激素缺乏症-评估
根据特定内分泌系统选择的候选基因突变
该家族/个体的表型。本研究的目的是
了解基因突变导致异常生长的机制。
异常生长原因的阐明--及特殊的紊乱
将使人们更好地了解
“正常”增长,并揭示了更大的问题,
人的属性(例如,身高是由基因决定的。校长
研究者目前拥有NIDDK资助的指导临床科学家
发展奖(K-08 DK 02569),截止到2002年6月30日,
额外的资金,以提高能力,完成目标,如本
和原始申请。
我们假设,一个子集的个人与生长障碍有一个
生长激素轴内的基因突变。经过详细的内分泌
评估,我们评估PROP-1,PIT-1,LHX 3,LHX 4,
生长激素释放激素(GHRH),GHRH受体(GHRHR),生长
激素促分泌素(GHS或GHSPIN),GHS受体(GHSR)和生长
激素(GH 1)。我们分析遗传连锁/单倍型不平衡,
鉴定候选基因,然后逐个外显子筛选,通过变性
高效液相色谱法(DHPLC)或单链构象
多态性分析(SSCA),然后直接测序构象独特的
一个家庭中受影响和未受影响的成员的外显子。然后我们确认突变
自动单核苷酸多态性(SNP)分析仪的状态,或
或者,通过使用限制性片段长度多态性
(RFLP)分析(必要时包括诱变)。突变的
然后将基因产物转染到适当的细胞系(例如,一
哺乳动物的生长激素或生长催乳激素),并表达以确定
导致特定的细胞紊乱。正如我们以前的工作所示,
用于表达特定细胞系对于获得生理学上
相关结果。基因组DNA和肿瘤cDNA都用作模板,
肿瘤组织中的突变分析,允许区分
生殖系和体细胞突变。这项补助金的一个新方面是充分的
从病人到激素再到DNA光谱分析
细胞系统。为了完成最初的工作,
已经开始,并将成为K-08剩余两年的主要重点
补助期。增加的资金将增加所有阶段的吞吐量,
增加人员和设备,提高主要研究者的
获得个人研究者研究补助金(R-01)的前景,以及
他的最终目标是成为一名独立调查员。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MICHAEL P WAJNRAJCH其他文献
MICHAEL P WAJNRAJCH的其他文献
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{{ truncateString('MICHAEL P WAJNRAJCH', 18)}}的其他基金
Molecular Pathophysiology of Human Growth Disorders
人类生长障碍的分子病理生理学
- 批准号:
6517919 - 财政年份:2001
- 资助金额:
$ 8.48万 - 项目类别:
ROLE OF GROWTH HORMONE RELEASING FACTOR IN SHORT STATURE
生长激素释放因子在身材矮小中的作用
- 批准号:
6309711 - 财政年份:1999
- 资助金额:
$ 8.48万 - 项目类别:
ROLE OF GROWTH HORMONE RELEASING FACTOR IN SHORT STATURE
生长激素释放因子在身材矮小中的作用
- 批准号:
6122549 - 财政年份:1998
- 资助金额:
$ 8.48万 - 项目类别:
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