BRAINIK · Identification and validation of cerebral KCa3.1/KCa2.3 potassium channels a drug tragets for the prevention and treatment of cerebral ischemia associated with diabetes and Alzheimers disease
FP7 — People (Marie Curie Actions)
- Duration
- 2012-10-01 → 2016-09-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Identification and validation of cerebral KCa3.1/KCa2.3 potassium channels a drug tragets for the prevention and treatment of cerebral ischemia associated with diabetes and Alzheimers disease
Ion channels KCa3.1 and related KCa2 regulate cellular functions by producing important electrical changes of the cell (hyperpolarization) and thereby regulate the actions of the crucial intracellular second messenger, calcium, and inflammatory activity in peripheral organs and the central nervous system. In the body and especially in the brain they are expressed in the vascular endothelium and in activated pro-inflammatory microglia (central immune system cells) and some neurons. Channel functions are altered in several disease states characterized by neurodegeneration and chronic inflammatory processes. From the medical perspective, such mechanisms can be relevant for the development and progression central pathologies caused ischemia (stroke) and microglia-mediated neuronal survival or loss. From the pharmacological perspective, we proposed KCa3.1 proteins as potential treatment targets and therefore we developed and patented innovative types KCa3.1 inhibitors (so called gating modulators; patent (PCT/ES2015/070662) and currently test their utilities to alleviate disease in preclinical experimental studies and in model cell systems of patients’ cells as translational approach. Moreover, for target validation and efficacy studies we generated a murine model of inducible KCa3.1-overexpression to reveal the pro-inflammatory nature of KCa3.1 and the channel’s role in neurodegeneration. Other “proof-of-concept” studies conducted so far revealed efficacy of our compounds in models rodent models of neurodegeneration, i.e. multiple sclerosis and amyotrophic lateral sclerosis. Moreover, we found improved learning and physical activity in healthy mice. To the contrary, in our murine model of overexpression of KCa3.1 resulted in strong inflammatory response in several organs and motoric alterations. In sum, these studies provide strong evidence for the disease-alleviating efficacy of KCa3.1-inhibitors for the treatment of neuroinflammation and –degeneration.
Data: CORDIS, © European Union
Project objective
The objectives of the project are to identify and evaluate potassium channels of the KCa3.1/KCa2.X type as novel drug targets for the prevention and treatment of cerebrovascular ischemia and neuroprotection in metabolic disease and neurodegenerative disorders associated with vascular pathologies, as a new pathophysiological concept and treatment strategy.To reach these aims, the proponent employs genetic models of ion channel deficiency and experimental models of human disease for pharmacological interventions with highly selective small molecule modulators and performs target identification studies on human material. The project will be conducted within the research frame of the Aragonese Institute of Health Sciences and in collaboration with clinical departments of the University Hospital Miguel Servet in Zaragoza, Spain, and the University Hospital Odense, Denmark, and with neuroscientists and pharmacologists at the University of Southern Denmark and the University of California, Davis, United States, for optimal scientific synergy and use of resources.The 1st and 2nd work packages consist of electrophysiological, molecular biological, and imaging studies using genetic and pharmacological tools for “target identification” in cerebrovasculature from murine and human diabetes mellitus type 2 (DM-2), Alzheimer disease (AD), and Morbus Fabry. The 3nd of work package consists of intervention trials and the testing the efficacy of recently developed small molecule modulators in mice models of DM-2 and AD for “target validation”. The 4th work package consists of epidemiological studies in which we define the genetic variability and polymorphisms in KCa3.1/KCa2.3 genes in Aragon Workers Health Study (AWHS)-cohort and evaluate their potential predictive value for disease.Our conceptually new approach and the outcome of our study may provide the rationale to develop small molecule modulators of KCa3.1/KCa2.X for the treatment of cerebrovascular and neurological disease.
Original text from CORDIS.
Participants
- INSTITUTO ARAGONES DE CIENCIAS DE LA SALUD · ZARAGOZACoordinatorSpain
Links
Data: CORDIS, © European Union