Descripción del proyecto
Dilucidar los mecanismos celulares y moleculares de la enfermedad de Alzheimer
Nuevos indicios sugieren la participación de tipos celulares distintos a las neuronas en la enfermedad de Alzheimer (EA o AD por sus siglas en inglés). Con todo, el estudio de células específicas y sus interacciones es difícil debido a la compleja diversidad celular del encéfalo. Los investigadores del proyecto AD_AGING_AND_GENDER, financiado con fondos europeos, trabajan sobre la hipótesis de que las alteraciones celulares y moleculares dependientes de la edad constituyen factores clave responsables del deterioro cognitivo. Los datos preliminares respaldan esta hipótesis y revelan la existencia de características moleculares que se superponen en la EA, el género y el envejecimiento. Los investigadores planean esclarecer aún más los mecanismos de la EA mediante el mapeo de las alteraciones celulares y moleculares responsables del desarrollo de la EA e identificar los posibles reguladores de la resiliencia patológica.
Objetivo
AlzheimerAlzheimer’s disease (AD) is a crucial problem in our society, raising the need for new therapeutic targets. Evidence suggests multiple non-neuronal cells are implicated in the systemic deficits of AD, but the complex cellular diversity in the brain hampers the investigation of specific cells and their interactions. Moreover, the course of the disease is highly variable, due to multiple risk factors, including aging and gender, which have overlapping molecular signatures with AD that might be further masking disease mechanisms.
I propose to expand the resolution from tissues to cellular environments, and to untangle overlapping molecular signatures of gender and aging, in order to unmask molecular mechanism of AD. Technological advances in genomics and imaging, including the single nucleus RNA-sequencing methods developed by me, as well as my expertise in computational analysis and CRIPSR perturbations, provide a unique opportunity to address this challenge. I obtained preliminary results strongly suggesting that multiple cell types are indeed altered in AD brains of mice and humans, and that gender, aging, and AD have overlapping molecular features. I hypothesize that age-dependent cellular/molecular alterations are key drivers of cognitive decline, and that the dynamics of these alterations determine risk and resilience levels in individuals.
We will test this hypothesis by: 1) Charting the cellular microenvironments and tissue topology of the human AD brain, to reveal cells, pathways, and cellular interactions driving AD; 2) Mapping the dynamic cellular/molecular trajectories in aging and AD in w.t. and AD mice, to untangle AD, aging, and gender dimorphism; and 3) Identifying regulators of cognitive resilience and decline in AD and aging, and connecting genes to function by detailed mechanistic investigations in vivo.
Overall, our innovative proposal is expected to advance our understanding of AD mechanism, and the link to aging and gender dimorphism.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
91904 Jerusalem
Israel