KIAA1199 and hyaluronic acid signaling: a promising therapeutic approach for glomerular disease
KIAA1199 和透明质酸信号传导:一种有前途的肾小球疾病治疗方法
基本信息
- 批准号:492766284
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:
- 资助国家:德国
- 起止时间:
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Glomerulosclerosis (secondary FSGS) is the common final pathway of most kidney diseases leading to chronic progressive renal failure (CKD). It affects 5-10% of the population worldwide. CKD is one of the most important independent risk factors for cardiovascular complications and premature death. In our previous work, we demonstrated that CKD is predominantly mediated by activated parietal cells in the context of secondary FSGS, and we therefore proposed activation of these cells as a novel therapeutic target. In preclinical studies, it has been shown by several international and independent research groups that inhibition of the collagen receptor DDR1 can prevent FSGS very effectively. However, the development of a specific DDR1 inhibitor has proven to be technically difficult/impossible. Therefore, in our preliminary joint work, we further investigated the possible mechanism of action of DDR1 in the kidney. We demonstrated that DDR1 activation induces the expression of the hyaluronidase KIAA1199. We show that this enzyme generates hyaluronic acid fragments with a specific and unusual molecular length of approximately 50 kDa (i.e. intermediate HA = intHA). Our pilot data suggest that these intHA fragments most likely play a key role in mediating FSGS - potentially via activation of parietal epithelial cells. The collaborative effort requested here brings together an interdisciplinary team of specialists: A crystallographer to identify highly specific small-molecule inhibitors (A.C.). A basic scientist with many years of experience in the biology of hyaluronic acids (J.S.). Human physicians and experts in FSGS with expertise in transgenic animal models (H.H., H.S., M.M.) and a nephropathologist (S.M.) for preclinical experiments on human biopsies. And finally, a pharmacologist with long experience in the DDR1 pathway and drug development (M.P.).Our extensive preliminary work has been generated in close scientific exchange. This demonstrates the high added value of our consortium and we hope that a significant contribution to the understanding of the biology of hyaluronic acid in glomerular diseases can be expected from this project. We are confident that our consortium will succeed in making an already known and highly effective signaling pathway (DDR1) accessible for clinical application in FSGS and CKD (direct translational application).
肾小球硬化(继发性FSGS)是大多数肾脏疾病导致慢性进行性肾功能衰竭(CKD)的共同终末途径。它影响了全世界5-10%的人口。CKD是心血管并发症和过早死亡的最重要的独立危险因素之一。在我们以前的工作中,我们证明了CKD主要是由激活的壁细胞介导的继发性FSGS的背景下,因此,我们提出激活这些细胞作为一种新的治疗靶点。在临床前研究中,几个国际和独立的研究小组已经表明,抑制胶原蛋白受体DDR 1可以非常有效地预防FSGS。然而,已经证明开发特异性DDR 1抑制剂在技术上是困难的/不可能的。因此,在我们的初步联合工作中,我们进一步研究了DDR 1在肾脏中的可能作用机制。我们证明,DDR 1激活诱导透明质酸酶KIAA 1199的表达。我们表明,这种酶产生的透明质酸片段具有特定的和不寻常的分子长度约50 kDa(即中间HA = intHA)。我们的试验数据表明,这些intHA片段很可能在介导FSGS中发挥关键作用-可能通过激活壁上皮细胞。这里要求的合作努力汇集了一个跨学科的专家团队:一个晶体学家来识别高度特异性的小分子抑制剂(A.C.)。在透明质酸生物学领域拥有多年经验的基础科学家(J.S.)。在转基因动物模型方面具有专业知识的人类医生和FSGS专家(H.H.,H. S.,M.M.)和肾脏病理学家(S.M.)用于人体活检的临床前实验。最后,一位在DDR 1途径和药物开发方面具有长期经验的药理学家(MP)。我们广泛的前期工作是在密切的科学交流中产生的。这证明了我们的财团的高附加值,我们希望这个项目可以为了解透明质酸在肾小球疾病中的生物学做出重大贡献。我们相信,我们的联盟将成功地使一个已知的和高度有效的信号通路(DDR 1)可用于FSGS和CKD(直接翻译应用)的临床应用。
项目成果
期刊论文数量(0)
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Professor Dr. Marcus Möller其他文献
Professor Dr. Marcus Möller的其他文献
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{{ truncateString('Professor Dr. Marcus Möller', 18)}}的其他基金
Preventive and translational nephrology
预防性和转化性肾病学
- 批准号:
446660122 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Heisenberg Grants
Ein neuer regenerativer Mechanismus im Glomerulus der Niere: Transdifferenzierung parietaler Epithelzellen
肾小球的新再生机制:壁上皮细胞的转分化
- 批准号:
32173405 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Research Grants
Die Bedeutung von FAT1 für die Ausbildung der Fußfortsätze und Schlitzmembran in Podozyten
FAT1对于足细胞足突和裂隙膜形成的重要性
- 批准号:
5422663 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Research Units
Untersuchung der molekularen Funktion eines neuen transmembranösen Proteins an der Schlitzmembran, dessen Mutation ein nephrotisches Syndrom auslöst.
研究裂隙膜上一种新的跨膜蛋白的分子功能,该蛋白的突变导致肾病综合征。
- 批准号:
5232934 - 财政年份:2000
- 资助金额:
-- - 项目类别:
Research Fellowships
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