SEMISYNTHETIC IGF-I/INSULIN HYBRIDS AS RECEPTOR PROBES
半合成 IGF-I/胰岛素杂交体作为受体探针
基本信息
- 批准号:2143173
- 负责人:
- 金额:$ 19.46万
- 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:1992-02-01 至 1997-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This proposal has long-term goals related to (a) identifying the
structural attributes of insulin-like growth factor I (IGF-I) which
determine its potency for interactions with type I IGF receptors, and its
consequent overall biological effects, (b) evaluating the development of
rules that might apply to the separate determinants of affinity and
selectivity for receptor interactions within structurally related groups of
ligands and receptors, and (c) considering the potential for development of
IGF-I analogs that might be of therapeutic or experimental value.
Specific aims for the project are summarized as follows: (a) To
prepare hybrid IGF-I/insulin analogs with selected structural changes and
amino acid replacements by chemical peptide synthesis and semisynthesis.
(b) To evaluate the potencies of these analogs with regard to their
abilities to bind to the type I IGF and insulin receptors through binding
competition studies and direct analysis of radiolabeled ligand binding. (c)
To consider the separate issues of receptor site affinity and selectivity
in relation to the IGF-I and insulin systems through comparisons of analog
interactions with both receptors. (d) To address aspects of potential
differences in the solution structures of analogs by spectroscopic methods
and chemical modification. (e) To evaluate the consequences of structural
changes in these analogs in relation to their biological activities in
vitro, by use of assays for 3H-thymidine incorporation into DNA and for
additional metabolic responses. (f) To evaluate the potential biological
implications of binding site heterogeneity in ligand interactions with the
type I IGF receptor through the kinetic analysis of related binding
studies. (g) To approach an understanding of type I IGF receptor
heterogeneity at the molecular level through use of chemical and affinity
methods.
As aberrations in IGF-I physiology can be expected to result
under different sets of circumstances in either inappropriately low or
inappropriately high rates of tissue growth, and as the IGF-I system could
be useful in by-passing the insulin system in states of insulin resistance,
it is not difficult to envision the potential health-related importance of
analogs of IGF-I that might (a) be selective for one or the other of its
actions, (b) be even more potent than the natural hormone, (c) inhibit the
action endogenous hormone by binding to receptor without inducing cellular
responses, or (d) act through multiple receptor systems to produce desired
metabolic effects. This proposal represents a study of the IGF-I system at
a fundamental level, at this stage, and the application of the methods of
chemical peptide synthesis and semisynthesis to the elucidation of relevant
structure-function relationships.
该提案的长期目标涉及:(a)确定
胰岛素样生长因子I(IGF-I)的结构属性,
确定其与I型IGF受体相互作用的效力,
(B)评价以下发展:
可能适用于亲和力的不同决定因素的规则,
在结构上相关的基团内的受体相互作用的选择性
配体和受体,以及(c)考虑开发
可能具有治疗或实验价值的IGF-I类似物。
该项目的具体目标概述如下:
制备具有选定结构变化的杂合IGF-I/胰岛素类似物,
通过化学肽合成和半合成进行氨基酸置换。
(b)为了评价这些类似物的效力,
通过结合I型IGF和胰岛素受体的能力
竞争研究和放射性标记配体结合的直接分析。(c)第(1)款
考虑受体位点亲和力和选择性的不同问题
与IGF-I和胰岛素系统相关,
与两种受体的相互作用。(d)为了解决潜在的
用光谱方法研究类似物溶液结构的差异
和化学修饰。(e)为了评估结构性的后果,
这些类似物的变化与其生物活性有关,
体外,通过使用3 H-胸苷掺入DNA和
额外的代谢反应。(f)为了评估潜在的生物学
在配体相互作用中结合位点异质性的影响
I型IGF受体相关结合动力学分析
问题研究(g)了解I型IGF受体
通过使用化学和亲和性,
方法.
由于IGF-I生理学的异常可能导致
在不同的情况下,无论是不适当的低,
不适当的高组织生长速率,并且由于IGF-I系统可以
可用于在胰岛素抵抗状态下绕过胰岛素系统,
不难想象,
IGF-I的类似物,其可能(a)对IGF-I的一种或另一种具有选择性,
作用,(B)甚至比天然激素更有效,(c)抑制
通过与受体结合而不诱导细胞内分泌,
反应,或(d)通过多个受体系统产生所需的
代谢效应 该提案代表了IGF-I系统的研究,
一个基本的水平,在这个阶段,和应用的方法,
化学多肽合成与半合成相关的阐明
结构-功能关系。
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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{{ truncateString('DONALD F STEINER', 18)}}的其他基金
CORE--CELLULAR/MOLECULAR BIOLOGY AND GENETIC STUDIES LABORATORY
核心--细胞/分子生物学和遗传学研究实验室
- 批准号:
6414879 - 财政年份:2000
- 资助金额:
$ 19.46万 - 项目类别:
CORE--CELLULAR/MOLECULAR BIOLOGY AND GENETIC STUDIES LABORATORY
核心--细胞/分子生物学和遗传学研究实验室
- 批准号:
6301042 - 财政年份:1999
- 资助金额:
$ 19.46万 - 项目类别:
CORE--CELLULAR/MOLECULAR BIOLOGY AND GENETIC STUDIES LABORATORY
核心--细胞/分子生物学和遗传学研究实验室
- 批准号:
6217559 - 财政年份:1999
- 资助金额:
$ 19.46万 - 项目类别:
CORE--CELLULAR/MOLECULAR BIOLOGY AND GENETIC STUDIES LABORATORY
核心--细胞/分子生物学和遗传学研究实验室
- 批准号:
6105110 - 财政年份:1999
- 资助金额:
$ 19.46万 - 项目类别:
CORE--CELLULAR/MOLECULAR BIOLOGY AND GENETIC STUDIES LABORATORY
核心--细胞/分子生物学和遗传学研究实验室
- 批准号:
6270504 - 财政年份:1998
- 资助金额:
$ 19.46万 - 项目类别:
CORE--CELLULAR/MOLECULAR BIOLOGY AND GENETIC STUDIES LABORATORY
核心--细胞/分子生物学和遗传学研究实验室
- 批准号:
6238759 - 财政年份:1996
- 资助金额:
$ 19.46万 - 项目类别:
SEMISYNTHETIC IGF-I/INSULIN HYBRIDS AS RECEPTOR PROBES
半合成 IGF-I/胰岛素杂交体作为受体探针
- 批准号:
2143174 - 财政年份:1992
- 资助金额:
$ 19.46万 - 项目类别:
SEMISYNTHETIC IGF-I/INSULIN HYBRIDS AS RECEPTOR PROBES
半合成 IGF-I/胰岛素杂交体作为受体探针
- 批准号:
2143175 - 财政年份:1992
- 资助金额:
$ 19.46万 - 项目类别:
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