Socratech L.L.C. is a start-up company within the University of Rochester founded in July 2000 with a focus on new vascular strategies for neurodegenerative disorders. The goal of this proposal is to establish and validate new stress-induced premature senescence (SIPS) model in brain endothelial cells (BEC) as a screening tool for drugs to selectively enhance functions of senescent brain endothelium in neurodegenerative disorders. Senescence has been associated with the aging disorders of the vascular system, e.g., atherosclerosis, diabetes, coronary disease, but its role in pathogenesis of neurodegenerative diseases is still not fully understood. The metabolically active senescent state is extremely stable, but numerous cellular functions are significantly diminished depending on the cell-type. Our preliminary data in SIPS-BEC suqqests specific defects in response to angiogenic stimulation and defects in lysosomal function. We hypothesize that senescent-related cellular dysfunctions in BEC could be selectively targeted to correct the underlying functional deficits. In support of this hypothesis, our preliminary data show that p38 MAPK inhibitor SB2902190 selectively improves angioqenic response of SIPS-BEC. Phase I will validate p38 MAPK pathway as a negative regulator of angiogenesis in senescent BEC and screen p38 MAP kinase inhibitors for improved angiogenic responses of SIPS-BEC (aim 1), and will validate selected lysosomal targets and preliminary screen lysosomotropic agents (aim 2). Phase II will extend studies with p38 MAPK inhibitors to animal models of accelerated senescence, and will determine their effects on cerebral blood flow, BBB functions, and development of brain capillary networks in vivo, and will focus to selectively correct lysosomal dysfunction, first in a SIPS-BEC model, and next in animal models of neurovascular storage disorders. The potential products ultimately to be developed are therapeutic drugs and genetic vectors to selectively correct dysfunctions of senescent brain endothelium in neurodegenerative disorders associated with impaired vascular regeneration and lysosomal dysfunction.