BIOLOGICAL EFFECTS OF BASIC CALCIUM PHOSPHATE CRYSTALS
BIOLOGICAL EFFECTS OF BASIC CALCIUM PHOSPHATE CRYSTALS
批准号:
2079295
负责人:
HERMAN S CHEUNG
金额:
$23.3万
依托单位国家:
美国
项目类别:
财政年份:
1995
资助国家:
美国
项目状态:
已结题
起止时间:
1995-09-30 至 1999-08-31
关键词:
articular cartilage calcium phosphate cartilage disorder cellular pathology chondrocytes citrates disease /disorder model drug delivery systems enzyme biosynthesis fibroblasts joint stiffness laboratory mouse laboratory rat macrophage metalloendopeptidases nonhuman therapy evaluation physical chemical interaction prostaglandin E skeletal disorder chemotherapy tissue /cell culture tumor necrosis factor alpha
中文摘要
描述:(改编自《调查者摘要》)钙-
含有晶体沉积疾病,包括钙
二水焦磷酸盐和碱性磷酸钙晶体是一种
一组临床上不同类型的关节炎,导致显著的
老年人的发病率。关节内含钙晶体
产生假性痛风的急性炎性发作以及
慢性退行性关节炎与软骨钙质沉着症和
密尔沃基肩部综合症。这些疾病的病因尚不清楚。
目前对病理性钙化机制的认识
是有限的,没有可靠的方法来防止钙结晶
沉积或影响吸收。总体目标是
确定退行性关节病相关的发病机制
在关节组织中沉积这些晶体,以便
制定一种合理的方法来防止或扭转
这样的证词。
这项建议的重点是细胞和钙之间的相互作用。
水晶。将特别强调要测试的实验:(1)
确定晶体如何激活细胞反应;(2)评估2
潜在的治疗药物--磷酸柠檬酸(PC)和前列腺素
(PG)El.需要检验的四个假设是:(1)晶体诱导
巨噬细胞合成和释放细胞因子,如肿瘤坏死
能加强晶体对滑膜细胞作用的因子-a
和/或诱导软骨细胞分泌导致软骨形成的酶
退化(旁分泌途径);(2)细胞被晶体激活
晶体表面与细胞膜的物理相互作用;
晶体诱导的金属蛋白酶的合成可以从
有丝分裂,是早期细胞反应的结果,例如蛋白质
(4)PC和PGEL是潜在的治疗药物
基于对含钙生物效应的了解
水晶。它们对晶体诱导的早期细胞反应的影响
将会被检查。一种新型缓释微载体作为一种
将测试PC的传输系统。成纤维细胞、软骨细胞和
巨噬细胞培养和小鼠进行性强直动物模型
用于研究。
英文摘要
DESCRIPTION: (Adapted from the Investigator's Abstract) Calcium-
containing crystal-deposition diseases, which include calcium
pyrophosphate dihydrate and basic calcium phosphate crystals, are a
group of clinically heterogeneous arthritides which cause significant
morbidity in the elderly. Intra-articular calcium-containing crystals
produce the acute inflammatory episodes of pseudogout as well as the
chronic degenerative arthritis associated with chondrocalcinosis and
Milwaukee Shoulder Syndrome. The etiology of these diseases is unknown.
As present understanding of the mechanisms of pathologic calcification
is limited, no reliable method exists to prevent calcium crystals
deposition or to effect resorption. The overall objective is to
determine the pathogenesis of the degenerative arthropathies associated
with the deposition of these crystals in articular tissues in order to
develop a rational means of preventing or reversing the consequences of
such deposition.
This proposal focuses on the interaction between cells and calcium
crystals. Specifically emphasized will be experiments to test: (1) to
determine how crystals activate cellular responses; (2) to evaluate 2
potential therapeutic agents, phosphocitrate (PC) and prostaglandin
(PG)El. Four hypotheses to be tested are: (1) crystals induce
macrophages to synthesize and release cytokines e.g. tumor necrosis
factor-a which can reinforce the action of crystals on synoviocytes
and/or induce chondrocytes to secrete enzymes leading to the cartilage
degeneration (paracrine pathway); (2) cell activation by crystals is due
to the physical interaction of crystal surface and cell membrane; (3)
crystal-induced metalloproteinase synthesis can be dissociated from
mitogenesis and is the result of early cellular responses e.g. protein
kinase C activation; (4) PC and PGEl are potential therapeutic agents
based on knowledge of the biologic effects of calcium-containing
crystals. Their effects on the early crystal-induced cellular responses
will be examined. A new form of sustained release microcarriers as a
delivery system for PC will be tested. Fibroblast, chondrocyte, and
macrophage cultures and a Murine Progressive Ankylosis animal model will
be used for the studies.
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海外基金