HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM
HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM
批准号:
2518402
负责人:
CHARLES W DANIEL
金额:
$20.18万
依托单位国家:
美国
项目类别:
财政年份:
1994
资助国家:
美国
项目状态:
已结题
起止时间:
1994-09-30 至 2000-08-31
中文摘要
内分泌乳房激素雌激素和黄体酮不仅正常
而且还有乳房肿瘤性生长。潜在的机制很差
理解但无疑涉及对组织中介的监管
例如胰岛素样生长因子(IGF),它们是促进
正常乳腺细胞在体外,并已被牵连在
这些细胞的不受控制的肿瘤性生长。使用缓释塑料
植入原位治疗小鼠乳腺的小区域,我们
最近证实了IGF与雌激素的局部协同刺激作用
导管生长。在使用的剂量下,无论是雌激素还是IGF-I
刺激了腺体。这种效果,伴随着丰富的
腺体中的IGF-I信息,有力地证明了IGF-I是正常的,
局部作用的导管乳房钼靶。
我们现在建议研究胰岛素样生长因子系统的局部激素调节。
并开发了一种全新的体内研究系统来做到这一点。
使用含有抗雌激素或抗孕酮的缓释植入物
消融同源受体的作用;局部阻断类固醇-
依赖的基因表达可以使用标准方法检测,例如
Northern杂交分析。将类固醇作用与
生长因子调控是理解腺体调控的关键
在正常和病态的情况下。事实上,这一点是
本提案所回应的RFA的重点。清晰的切割能力
我们的系统将类固醇/生长因子的调节
在初步研究中描述了直截了当、毫不含糊的方式。
因此,该系统承诺直接回答许多问题,包括
雌激素和孕激素对正常范围内IGF系统的调节,
癌前病变和肿瘤性腺体。
这一新方法将用于研究雌激素和黄体酮。
IGF-I、IGF-II、IGF-1和IGF-2受体以及
体内某些IGF结合蛋白。预计将公布的细节
旁分泌的激素调节和IGF的负反馈调节
行动将成为焦点。特定的生长调节功能
结合蛋白,从上述实验中推断将进一步
通过植入突变形式的免疫球蛋白来扰乱正常活动和
取消本地操作的掩码。我们将基因表达与良好的-
腺体内明确的、生物相关的终点(导管生长
相对于抑制),意味着关于功能的强烈推论
胰岛素样生长因子系统的激素调节的重要性即将到来。
英文摘要
The endocrine mammogens estrogen and progesterone drive not only normal
but also neoplastic mammary growth. Underlying mechanisms are poorly
understood but no doubt involve the regulation of tissue intermediaries
such as Insulin-like Growth Factors (IGFs) which are potent mitogens for
normal mammary cells in vitro and have been implicated in the
uncontrolled, neoplastic growth of these cells. Using slow-release plastic
implants to treat small regions of the mouse mammary gland in situ, we
recently demonstrated localized synergy of IGF with estrogen to stimulate
ductal growth. At the doses used, neither estrogen or IGF-I alone
stimulated the gland. This effect, along with the presence of abundant
IGF-I message in the gland, is strong evidence that IGF-I is a normal,
locally-acting ductal mammogen.
We now propose to investigate local hormonal regulation of the IGF system
and have developed a completely novel in vivo research system to do so.
Slow-release implants containing antiestrogen or antiprogesterone are used
to ablate cognate receptor action; localized disruption of steroid-
dependent gene expression is detectable using standard methods such as
Northern hybridization analysis. The capacity to relate steroid action to
growth factor regulation is crucial to understanding glandular regulation
in normal and pathological circumstances. Indeed, this single point is the
focus of the RFA to which this proposal responds. The clearcut capability
of our system to link steroid/growth factor modulation in a
straightforward, unambiguous manner is described in preliminary studies.
This system therefore promises direct answers to many questions concerning
estrogen and progesterone regulation of the IGF system within the normal,
preneoplastic and neoplastic gland.
This new approach will be used to investigate estrogen and progesterone
regulation of IGF-I, IGF-II, IGF type 1 and type 2 receptors, as well as
certain IGF binding proteins in vivo. It is expected that the details of
hormonal regulation of paracrine and negative feedback regulation of IGF
action will come into focus. Growth-regulatory functions for specific
binding proteins, inferred from the above experiments will be further
defined by implanting mutant forms of IGI to perturb normal activity and
unmask local actions. Our ability to relate gene expression to well-
defined, biologically relevant end points within the gland (ductal growth
versus inhibition), means that strong inferences concerning the functional
importance of hormonal regulation of the IGF system will be forthcoming.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
Progesterone receptors in the mouse mammary duct: distribution and developmental regulation.
小鼠乳腺导管中的孕酮受体:分布和发育调节。
DOI:
--
发表时间:
1996
期刊:
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.
影响因子:
--
作者:
[Silberstein,GB, VanHorn,K, Shyamala,G, Daniel,CW]
通讯作者:
Daniel,CW
Gordon Research Conference on Mammary Gland Biology
-
批准号:6318031
-
项目类别:
-
资助金额:$0.7万
-
财政年份:2001
-
负责人:CHARLES W DANIEL
-
依托单位:
Gordon Research Conference on Mammary Gland Biology
-
批准号:6514943
-
项目类别:
-
资助金额:$0.7万
-
财政年份:2001
-
负责人:CHARLES W DANIEL
-
依托单位:
HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM
-
批准号:2149390
-
项目类别:
-
资助金额:$17.83万
-
财政年份:1994
-
负责人:CHARLES W DANIEL
-
依托单位:
HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM
-
批准号:2328583
-
项目类别:
-
资助金额:$6.6万
-
财政年份:1994
-
负责人:CHARLES W DANIEL
-
依托单位:
HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM
-
批准号:2149391
-
项目类别:
-
资助金额:$18.56万
-
财政年份:1994
-
负责人:CHARLES W DANIEL
-
依托单位:
HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM
-
批准号:2016878
-
项目类别:
-
资助金额:$19.4万
-
财政年份:1994
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY REGULATION BY TRANSFORMING GROWTH FACTOR BETA
-
批准号:3188279
-
项目类别:
-
资助金额:$16.86万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY REGULATION BY TRANSFORMING GROWTH FACTOR-BETA
-
批准号:3188277
-
项目类别:
-
资助金额:$13.89万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY GROWTH REGULATION: TRANSFORMING GROWTH FACTOR-B
-
批准号:2200678
-
项目类别:
-
资助金额:$18.69万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY GROWTH REGULATION: TRANSFORMING GROWTH FACTOR-B
-
批准号:3329512
-
项目类别:
-
资助金额:$17.67万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY GROWTH REGULATION: TRANSFORMING GROWTH FACTOR-B
-
批准号:3329514
-
项目类别:
-
资助金额:$13.41万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY REGULATION BY TRANSFORMING GROWTH FACTOR-BETA
-
批准号:3188278
-
项目类别:
-
资助金额:$16.37万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY GROWTH REGULATION: TRANSFORMING GROWTH FACTOR-B
-
批准号:2200679
-
项目类别:
-
资助金额:$19.78万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
MAMMARY GROWTH REGULATION: TRANSFORMING GROWTH FACTOR-B
-
批准号:3329513
-
项目类别:
-
资助金额:$18.42万
-
财政年份:1987
-
负责人:CHARLES W DANIEL
-
依托单位:
AGING OF MAMMARY CELLS
-
批准号:3114152
-
项目类别:
-
资助金额:$6.71万
-
财政年份:1979
-
负责人:CHARLES W DANIEL
-
依托单位:
AGING OF MOUSE MAMMARY CELLS
-
批准号:3114154
-
项目类别:
-
资助金额:$18.56万
-
财政年份:1979
-
负责人:CHARLES W DANIEL
-
依托单位:
AGING OF MOUSE MAMMARY CELLS
-
批准号:3114151
-
项目类别:
-
资助金额:$10.08万
-
财政年份:1979
-
负责人:CHARLES W DANIEL
-
依托单位:
AGING OF MOUSE MAMMARY CELLS
-
批准号:3114153
-
项目类别:
-
资助金额:$16.78万
-
财政年份:1979
-
负责人:CHARLES W DANIEL
-
依托单位:
海外基金