Recovery from Cachexia in Heart and Skeletal Muscle

心脏和骨骼肌恶病质的恢复

基本信息

批准号：
7656574
负责人：
KARL T WEBER
金额：
$ 37万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-14 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7656574
关键词：
Abdomen Acetylcysteine Address Affect Aftercare Aldosterone Aldosterone Receptors Amlodipine Anabolic Agents Antioxidants Apoptosis Ascites Assisted Circulation Atrophic Attenuated Bed rest Biochemical Biochemistry Body Weight Cachexia Calcium-Sensing Receptors Cardiac Chronic Clinical Congestive Heart Failure Device Removal Devices Effectiveness Event Gene Expression Gene Expression Profile Genome Growth Factor Health Heart Heart failure Hormones Infusion procedures Insulin Intervention Investigation Kidney Left Mediating Medical Mineralocorticoid Receptor Modeling Molecular Morphology Muscle Muscular Atrophy Myocardium Natural regeneration Necrosis Operative Surgical Procedures Outcome Oxidative Stress Oxidative Stress Induction Parathyroid Hormones Parathyroid gland Pathologic Pathway interactions Patients Peptide Hydrolases Perfusion Plant Roots Rattus Recovery Renal Blood Flow Renin-Angiotensin-Aldosterone System Reporting Role Secondary Hyperparathyroidism Signs and Symptoms Skeletal Muscle Sodium Chloride Spironolactone Staging Structure Swelling Syndrome Time Tissues Treatment Protocols Ubiquitin Upper Extremity Water Withdrawal channel blockers cinacalcet eplerenone heart dimension/size human PTH protein insight interest muscular structure novel outcome forecast pre-clinical prevent public health relevance receptor receptor binding response soft tissue ventricular assist device wasting

项目摘要

DESCRIPTION (provided by applicant): Background. Congestive heart failure (CHF) is a systemic illness. Rooted in neurohormonal activation, it features oxidative stress and a wasting of soft tissues eventuating in cachexia, generally considered irreversible. However, prolonged bed rest leads to a sustained recovery from CHF and normalization in heart size; so too does a left ventricular assist device. Mechanisms involved in the recovery from cachexia are of interest. The role of neurohormonal withdrawal could be inferred but is not defined. Preliminary studies in cachectic rats receiving 4 wks aldosterone/salt treatment (ALDOST) identified altered transcriptome of heart and skeletal muscle that included upregulated ubiquitin-specific protease2 and downregulated insulin growth factor (IGF)-1. A natural recovery in body weight and atrophic muscle occurred over 4 wks with the discontinuation of ALDOST, and an assisted recovery when ALDOST was continued and supplemented with an ALDO receptor antagonist, spironolactone (Spiro), for 4 wks. Hypothesis. The wasting seen at wk 4 of chronic ALDOST can be reversed by its discontinuation, by cotreatment with agents interfering with either aldosterone receptor binding, Ca2+ overloading, or oxidative stress, or by an anabolic agent alone or in combination with eplerenone (Epler), a selective ALDO receptor antagonist. Recovery from gene expression abnormalities should give us insights into the effectiveness and shortcomings of each agent. Plan. We will use the ALDOST model (in which parathyroid hormone-mediated intracellular Ca2+ overloading with induction of oxidative stress has been demonstrated during a preclinical stage (wk 1) followed by cachexia (wk 4)) to address the progression of molecular events leading to cachexia. Neurohormonal abnormality, caused by ALDOST, can be readily discontinued. Gene expression arrays allow us to reveal pathways leading to cachexia and to what extent abnormalities in heart and skeletal muscle genome, biochemistry and structure are reversed by each treatment. Aim #1: to characterize biochemical and gene expression abnormalities at preclinical (wk 1) and pathologic (wk 4) stages of chronic ALDOST in cardiac and skeletal muscle, together with their potential for natural recovery by discontinuing ALDOST after 4 wks; and to compare this reversal to assisted recovery when 6 and 8 wks ALDOST includes 2 or 4 wks of Spiro or Epler cotreatment begun at wk 4. Aim#2: to characterize recovery and molecular events in diseased heart and skeletal muscle at wks 6 and 8 ALDOST in response to assisted recovery provided by attenuated intracellular Ca2+ overloading using a) cinacalcet, a calcimimetic that resets the parathyroid glands' Ca2+- sensing receptor to suppress secondary hyperparathyroidism (SHPT), b) amlodipine, an L-type Ca2+ channel blocker that prevents Ca2+ entry in the setting of SHPT, and c) by negating oxidative stress with N-acetylcysteine, an antioxidant, each begun at wk 4. Aim #3: to determine whether molecular evidence of recovery would appear in the transcriptome and structure of diseased cardiac and skeletal muscle, when 4 wks treatment with an anabolic agent is introduced at wk 4 ALDOST, using an infusion of IGF-1, given alone or with Epler. Congestive heart failure (CHF) is a major health problem. Advanced CHF accompanied by neurohormonal activation and a wasting of tissues, or cachexia, carries an ominous prognosis and is thought to be irreversible. This study will address molecular mechanisms involved in the recovery from cachexia that appears in rats treated with aldosterone/salt and where recovery from this regimen can be achieved by its withdrawal or pharmacologic intervention. PUBLIC HEALTH RELEVANCE: Congestive heart failure (CHF) is a major health problem. Advanced CHF accompanied by neurohormonal activation and a wasting of tissues, or cachexia, carries an ominous prognosis and is thought to be irreversible. This study will address molecular mechanisms involved in the recovery from cachexia that appears in rats treated with aldosterone/salt and where recovery from this regimen can be achieved by its withdrawal or pharmacologic intervention.

描述（由申请人提供）：背景。充血性心力衰竭（CHF）是一种全身性疾病。它根源于神经激素激活，其特点是氧化应激和软组织消耗，最终导致恶病质，通常被认为是不可逆转的。然而，长期卧床休息可以使慢性心力衰竭持续恢复，并使心脏大小恢复正常；左心室辅助装置也是如此。恶病质恢复的机制令人感兴趣。可以推断神经激素撤退的作用，但尚未定义。对接受 4 周醛固酮/盐治疗 (ALDOST) 的恶病质大鼠进行的初步研究发现，心脏和骨骼肌的转录组发生了改变，其中包括泛素特异性蛋白酶 2 上调和胰岛素生长因子 (IGF)-1 下调。停止 ALDOST 后 4 周内体重和萎缩肌肉自然恢复，继续 ALDOST 并补充 ALDO 受体拮抗剂螺内酯 (Spiro) 4 周后可辅助恢复。假设。慢性 ALDOST 第 4 周出现的消耗可通过停药、与干扰醛固酮受体结合、Ca2+超载或氧化应激的药物联合治疗、单独使用合成代谢药物或与依普利农 (Epler) 联合治疗来逆转。选择性 ALDO 受体拮抗剂。从基因表达异常中恢复应该让我们深入了解每种药物的有效性和缺点。计划。我们将使用 ALDOST 模型（其中甲状旁腺激素介导的细胞内 Ca2+ 超载并诱导氧化应激已在临床前阶段（第 1 周）和恶病质（第 4 周）得到证实）来解决导致恶病质的分子事件的进展。由 ALDOST 引起的神经激素异常可以很容易地停药。基因表达阵列使我们能够揭示导致恶病质的途径，以及每种治疗在多大程度上逆转心脏和骨骼肌基因组、生物化学和结构的异常。目标#1：表征心肌和骨骼肌慢性 ALDOST 临床前（第 1 周）和病理（第 4 周）阶段的生化和基因表达异常，以及 4 周后停止 ALDOST 后自然恢复的潜力；并将这种逆转与第 6 周和第 8 周时的辅助恢复进行比较，ALDOST 包括从第 4 周开始的 2 周或 4 周 Spiro 或 Epler 联合治疗。目标#2：描述第 6 周和第 8 周时患病心脏和骨骼肌的恢复和分子事件ALDOST 是通过使用 a) 西那卡塞（一种模拟钙剂，可重置细胞内 Ca2+ 超载）来响应辅助恢复的甲状旁腺的 Ca2+ 感应受体抑制继发性甲状旁腺功能亢进 (SHPT)，b) 氨氯地平，一种 L 型 Ca2+ 通道阻滞剂，可防止 SHPT 情况下的 Ca2+ 进入，以及 c) 通过使用 N-乙酰半胱氨酸（一种抗氧化剂）消除氧化应激，每个都在第 4 周开始。目标 #3：确定在治疗 4 周时，患病心脏和骨骼肌的转录组和结构中是否会出现恢复的分子证据在第 4 周 ALDOST 中引入合成代谢药物，使用 IGF-1 输注，单独给药或与 Epler 一起给药。充血性心力衰竭（CHF）是一个主要的健康问题。晚期CHF伴有神经激素激活和组织消耗或恶病质，预后不祥，并且被认为是不可逆转的。这项研究将探讨用醛固酮/盐治疗的大鼠中出现的恶病质恢复所涉及的分子机制，以及可以通过停药或药物干预来实现该方案的恢复。公众健康相关性：充血性心力衰竭 (CHF) 是一个主要的健康问题。高级 CHF 伴随神经激素激活和组织消耗或恶病质会带来不祥的预后，并且被认为是不可逆转的。这项研究将探讨用醛固酮/盐治疗的大鼠中出现的恶病质恢复所涉及的分子机制，以及可以通过停药或药物干预来实现该方案的恢复。