Harvard Catalyst Profiles

NIH

Role of Microglia in Retinitis Pigementosa

Role Description: NIH R01EY027921 (PI:Weiner/Co-PI: Butovsky) Role: Co-PI. The focus of this grant proposal is to characterize retinal microglia and how they regulate and/or participate in retinal damage in both animal models of retinitis pigmentosa and in eyes from human subjects. We will investigate whether retinitis pigmentosa in animal models can be treated by specifically targeting and modulating microglia. We will use new technology and approaches to understand features of microglia cells that can then be exploited to develop novel microglia-targeting therapies to treat humans with retinitis pigmentosa.

Role: Principal Investigator

NIH

Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer’s disease

Role Description: Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer’s disease NIH/NIA R01 AG054672-01 (Butovsky) Role: PI. We hypothesize that danger signals (dead neurons and amyloid-ß peptides) alter functional phenotype of innate immune cells from the homeostatic (M0) to newly discovered neurodegenerative (MGnD) phenotype. We will address our hypothesis in the following aims: 1) targeting Trem2-induced Apoe/miR155 pathway to restore M0-homeostatic microglia in AD mouse models. We will specifically delete miR-155, Apoe and Trem2 in microglia of AD mouse models; 2) restoration of M0-homeostatic microglia via Mertk pathway in humanized APOE4 and AD mice. We will specifically over-express Mertk in microglia of APOE4 humanized mice and AD mouse models. We will validate our findings by investigating AD brains from prodromal to advanced stages. The goal of our investigations is to define new molecular mechanisms of immune and inflammatory processes that contribute to the development and progression of AD, which in turn will provide a basis for new approaches for immune based therapy of the disease.

Role: Principal Investigator

Cure Alzheimer’s Fund

The role of APOE in microglia regulation in neurodegeneration

Role Description: We hypothesize that danger signals (dead neurons, dystrophic axons and amyloid-ß peptides) induce APOE signaling, which alters functional phenotype of microglia from the homeostatic (M0) to neurodegenerative MGnD) phenotype in a gender-dependent manner. We will address the hypothesis in the following aims: 1) determine the role of human APOE isoforms in microglia regulation in a gender-dependent manner in aging and mouse models of neurodegeneration (Holtzman/Greengard collaboration); 2) investigate how APOE isoforms affect phenotype and function of recruited human inflammatory monocytes (Bu/Wellington collaboration).

Role: Principal Investigator

NIH

Identification of MicroRNA and Proteomics in immune cells and plasma in ALS

Role Description: NIH/NINDS R21 NS101673 (Butovsky) Role: PI. We hypothesize that abnormalities in miRNA and proteomic signatures in ALS may serve as immune-based biomarkers of disease progression and may reveal new targets for immune-modulation to slow ALS. Our objective will be addressed in aims 1) identification of miRNA and proteomic signature in sALS and fALS progression; and 2) replication and validation of the identified hits.

Role: Principal Investigator

NIH

Microglial mechanisms of postoperative CNS inflammation and cognitive decline

Role Description: Microglial mechanisms of postoperative cognitive decline NIH/NIA R01 AG051812-02 (PI: Crosby/Co-PI: Butovsky) Role: MPI. The goal of this project is to investigate microglial involvement in the cognitive after-effects of general anesthesia and surgery in old subjects.

Role: Principal Investigator

NIH

Restoration of homeostatic microglia in CNS inflammation

Role Description: Mechanism of regulation of CNS inflammation by microglia NIH/NINDS R01 NS088137-02 (Butovsky) Role: PI. The goals of this project are 1) to determine the specific molecular and functional properties of microglia during processes of tissue injury and repair that characterizes MS; and 2) to define a strategy whereby specific targeting of microglia can be used to reduce compartment-specific immune injury and promote repair in MS by restoring microglial unique molecular signature and function.

Role: Principal Investigator