CARDIAC HYPERTROPHY AND SERCA2 GENE EXPRESSION
心脏肥大和 SERCA2 基因表达
基本信息
- 批准号:6476963
- 负责人:
- 金额:$ 30.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1995
- 资助国家:美国
- 起止时间:1995-08-01 至 2003-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adenoviridae calcium transporting ATPase cardiac myocytes enzyme activity gene induction /repression genetically modified animals heart contraction heart enlargement heart failure intracardiac pressure laboratory mouse laboratory rabbit laboratory rat molecular cloning phospholamban ribosomes sarcoplasmic reticulum transcription factor transfection /expression vector
项目摘要
Heart failure (HF) is an important clinical problem and abnormalities
in Ca2+ handling are considered to be a significant contributor to
cardiac dysfunction. Decreased activity of the Ca2+ ATPase of the
sarcoplasmic reticulum (SERCA2) occurs in failing hearts. Increasing
SERCA2 activity through SERCA2 transgene expression may, therefore,
improve cardiac function. In Aim I, we will evaluate if pressure
overload (PO) induced decreases in SERCA2 activity, abnormalities in
Ca2+ handling, and contractile function can be prevented and compensated
for in SERCA2 transgenic animals. PO-induced decreases in SERCA2 could
only be obtained in rats and not in mice. We, therefore, produced
SERCA2 transgenic rats which will be submitted to PO by aortic
constriction (AC). We will determine in these SERCA2 rats if the PO-
induced decrease in SERCA2 levels and activity and resultant
abnormalities in Ca2+ handling and contractile function can be
prevented. SERCA2 activity can also be increased by diminishing the
inhibitory influence of unphosphorylated phospholamban (PLB). This
approach will be pursued in Aim II by expressing mutant PLB with
decreased SERCA2 interaction and by decreasing PLB levels using an anti-
PLB ribozyme construct in isolated cardiac myocytes and in transgenic
animals. Using an anti-SERCA2 ribozyme approach, SERCA2 levels by
themselves can be lowered to determine the role of diminished SERCA2 in
the induction of heart failure. In Aim III, we will explore if
decreases in SERCA2 levels and other potential consequences of PO
persisting for some time can subsequently be increased and result in
improvement of Ca2+ handling and contractile performance. Hearts from
rats with PO persisting for some time and developing heart failure will
be used for viral vector mediated expression of SERCA2 and PLB related
transgenes. SERCA2 activity, Ca2+ handling, and contractile function
will be assessed in myocytes, papillary muscle strips from such hearts
to determine if functional restoration can occur. Our findings will
provide new knowledge related to the role which lowered SERCA2 activity
plays in the development of HF and if maintaining or increasing SERCA2
activity can improve cardiac function and play a potential role in the
treatment of HF.
心力衰竭(HF)是一个重要的临床问题和异常
在Ca 2+处理被认为是一个重要的贡献者,
心功能不全 Ca 2 + ATP酶活性降低
肌浆网(SERCA 2)发生在衰竭的心脏中。 增加
因此,通过SERCA 2转基因表达的SERCA 2活性可能,
改善心脏功能。在目标I中,我们将评估压力是否
超负荷(PO)诱导SERCA 2活性降低,
Ca 2+处理和收缩功能可以被预防和补偿
在SERCA 2转基因动物中。 PO诱导的SERCA 2减少可能
仅在大鼠中获得,而在小鼠中不获得。 因此,我们制作了
SERCA 2转基因大鼠,将通过主动脉给药进行PO
收缩(AC)。 我们将在这些SERCA 2大鼠中确定PO-
诱导SERCA 2水平和活性降低,
Ca 2+处理和收缩功能的异常可能是
防止。 SERCA 2活性也可以通过减少
未磷酸化受磷蛋白(PLB)的抑制作用。这
在Aim II中,通过表达突变型PLB,
降低SERCA 2相互作用,并通过使用抗-
PLB核酶在分离心肌细胞中的构建和转基因心肌细胞中的表达
动物 使用抗SERCA 2核酶方法,通过免疫荧光法测定SERCA 2水平。
可以降低它们本身,以确定减少的SERCA 2在
导致心力衰竭 在Aim III中,我们将探讨
SERCA 2水平降低和PO的其他潜在后果
持续一段时间后,可能会增加,并导致
Ca 2+处理和收缩性能的改善。的心自
PO持续一段时间并发展为心力衰竭的大鼠将
用于病毒载体介导的SERCA 2和PLB相关基因的表达
转基因 SERCA 2活性、Ca 2+处理和收缩功能
将在来自这些心脏的肌细胞、乳头肌条中评估
以确定是否可以发生功能恢复。 我们的发现将
提供与降低SERCA 2活性的作用相关的新知识
在HF的发展中起作用,如果维持或增加SERCA 2
活动可以改善心脏功能,并在
HF的治疗
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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Wolfgang H Dillmann其他文献
Wolfgang H Dillmann的其他文献
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{{ truncateString('Wolfgang H Dillmann', 18)}}的其他基金
Heart Vascular Function and Thyroid Hormone Receptors
心脏血管功能和甲状腺激素受体
- 批准号:
8140390 - 财政年份:2011
- 资助金额:
$ 30.03万 - 项目类别:
Heart Vascular Function and Thyroid Hormone Receptors
心脏血管功能和甲状腺激素受体
- 批准号:
8262605 - 财政年份:2011
- 资助金额:
$ 30.03万 - 项目类别:
Heart Vascular Function and Thyroid Hormone Receptors
心脏血管功能和甲状腺激素受体
- 批准号:
8398969 - 财政年份:2011
- 资助金额:
$ 30.03万 - 项目类别:
Heart Vascular Function and Thyroid Hormone Receptors
心脏血管功能和甲状腺激素受体
- 批准号:
8696825 - 财政年份:2011
- 资助金额:
$ 30.03万 - 项目类别: