Abstract Ischemic stroke is a leading cause of death and long-term disability worldwide, and other than reperfusion therapy, almost no treatment is available. Thus, there is an urgent need for new stroke therapies, particularly those that demonstrate efficacy in the elderly, when most strokes occur. Mounting evidence indicates that proteostasis-based therapeutics have great potential in treating aging- and/or ischemia-related diseases that are characterized by a disrupted proteome. Especially, the unfolded protein response (UPR), which comprises multiple adaptive response pathways that facilitate recovery of proteostasis, has been increasingly recognized as a highly promising therapeutic target for neurodegenerative and ischemic diseases. The UPR is activated when the proteome in the endoplasmic reticulum (ER), a key organelle for protein folding and maturation, is perturbed, a condition called ER stress. The primary purpose of the UPR is to restore cellular proteostasis and promote cell survival. The UPR has 3 major branches, named after 3 ER stress sensor proteins: ATF6 (activating transcription factor 6), IRE1(inositol-requiring enzyme 1), and PERK (protein kinase RNA-like ER kinase). It is well known that ischemic stroke causes ER stress and activates the UPR. Importantly, our extensive data have established that activation of the UPR in neurons during the acute stroke phase is neuroprotective, strongly endorsing the therapeutic potential of the UPR in ischemic stroke. But, to develop safe and effective UPR-based pharmacologic interventions in stroke, we must further know 1) how the UPR affects other brain cell types, especially astrocytes – the most abundant cell subtype in the brain, and 2) how UPR modulation impacts long- term stroke outcome. Thus, the objectives of this renewal proposal are to determine the astrocytic role of the individual UPR branches in stroke pathophysiology, and to assess the therapeutic potential of targeting the UPR in stroke using young and aged animals. Our overarching hypothesis is that the individual UPR branches influence stroke outcome in a cell- and phase-specific manner and thus, must be harnessed accordingly for optimal UPR-based therapeutic strategies in stroke. Guided by our preliminary data, and also inspired by exciting advances in the field, we will pursue 3 specific aims: 1) Determine the role of the ATF6 UPR branch in ischemic stroke; 2) Determine the role of the IRE1/XBP1 UPR branch in ischemic stroke; 3) Determine the role of the PERK UPR branch in ischemic stroke. The proposed research is significant because we expect to clarify the role of each astrocytic UPR branch in stroke, and to determine the effects of pharmacologic modulation of the UPR on stroke outcome in the context of stroke phase and aging. Such knowledge will be fundamental to informing the development of new UPR-based strategies aimed to improve quality of life for stroke patients.