Wednesday, November 30, 2022
11/30/2022
OVERALL – ABSTRACT SUMMARY This P01— Strategies for Targeting Astrocyte Reactivity in AD and ADRD (STAR-ADRD) addresses the (patho)physiologic roles of reactive astrocytes in Alzheimer’s disease (AD) and related dementias (ADRD). Though highly significant to many disease phenotypes, astrocyte functions are under-investigated and have yet to benefit from large-scale programmatic support from the NIH. To fill this void we have assembled a highly accomplished and collaborative team from the University of Kentucky Sanders-Brown Center on Aging (UK- SBCoA). The overarching goals of this project are to: (1) Use cell-specific targeting to modulate distinct aspects of the reactive astrocyte phenotype. (2) Use cutting-edge technologies to assess the functional impact of reactive astrocytes in intact preclinical mouse models of AD and ADRD pathologies. (3) Leverage UK-SBCoA and UK- Alzheimer’s Disease Research Center (ADRC) resources to validate preclinical results in postmortem and living human subjects. And (4) Use an integrated data pipeline approach to analyze and interpret data within and across projects. Through these aims we will test the hypothesis that: interrelated reactive astrocyte phenotypes drive major pathophysiologic features of dementia including cerebrovascular dysfunction, hypometabolism, and impaired neuronal network function and fidelity. Projects are designed around a clear understanding that dementia does not exist as a single pathological entity most of the time, but rather is characterized by multiple brain pathologies. Project 1 (Astrocytic end-feet and VCID) will use MMP9 overexpression/knockdown in a model of cerebral small vessel disease to address astrocyte endfeet degeneration. Project 2 (Astrocytic insulin signaling and AD) will overexpress/knockdown astrocytic insulin receptors (IR) in an Aß model to study the impact of impaired astrocytic IR signaling. Project 3 (Astrocytic glutamate transport in AD and VCID) will overexpress/knockdown the astrocytic glutamate transporter SLC1A2 in a mixed Aß-vascular model to assess the role of impaired glutamate transport in reactive astrocytes. Project 4 (Astrocytic KATP channels in LATE+HS) will overexpress/eliminate astrocytic ABCC9/SUR2 in a model of LATE + hippocampal sclerosis to assess the role of KATP channels. Four Cores will support and further integrate our Projects. Core B: Animal Vascular-Metabolic-Neural Network (VMN) will assess cerebrovascular, metabolic, and neural network properties in mice using two-photon microscopy, MRI/MRS, microelectrode array neuro- chemistry, and electrophysiology. Core C: Human Consultation-Biosamples-Biomarkers (CBB) will validate results in mice using well characterized autopsy tissue, MRI, EEG, and fluid biomarker data from humans. And Core D: Data Management and Biostatistics will establish a data pipeline for efficient categorization, transformation, and statistical analysis of complex relationships between astrocyte interventions and endpoint measures, within and between projects. Finally, an Administrative Core (Core A) will provide leadership, coordination, integration, and administrative structure, so that the P01 goals are achieved.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
