NINDS - National Institute of Neurological Disorders and Stroke
Transient global ischemia in rodents (2 vessel occlusion in mice, 2VO) induces delayed death of hippocampal CA1 neurons and is a model for human ischemic brain injury and long lasting hippocampal memory deficits. Events that occur before neuronal death include caspase and pro-apoptotic Bcl-2 family member (Bax) activation, cleavage of the anti-death Bcl-2 family protein Bcl-xL, cellular Ca2+ dysregulation and large conductance mitochondrial channel activity. The opening of a large conductance, Ca2+ dependent, inner mitochondrial membrane channel occurs early during the injury phase, therefore the identification and targeting of this inner membrane channel has long been an important goal of both basic research and clinical communities. The inner membrane channel is known as the mitochondrial permeability transition pore (mPTP). It is activated by neuronal Ca2+ dysregulation and by the binding of the mitochondrial peptidyl-prolyl cis-trans isomerasecyclophilin D (CypD). It has been reported that CypD binds to the stator region of the ATP synthase at the OSCP subunit. CypD binding is inhibited by the well-known mPTP inhibitor cyclosporine A (CsA), which attenuates mPT channel activation. During a previous funding period, we were the first to demonstrate that the ATP synthase membrane-embedded c-subunit forms the largest known channel of the mPTP, the ATP synthase c-subunit leak channel (ACLC), and we showed that CsA inhibits ACLC activity by binding within the ATP synthase F1/stator portion because channel inhibition fails to occur when the membrane portions of the ATP synthase are chemically stripped of the F1/stator components. We also reported that Dexpramipexole (Dex) is a safe modulator of ATP synthase leak that binds directly to OSCP/subunit b on the stator complex. Dex ameliorates disease in neurodevelopmental brain disorder models. In this most recent funding period, we created a mutation of the c- subunit to reduce channel activity; we successfully reduced channel activity, preventing mitochondrial permeability transition (mPT) in vitro and in in vivo ischemic brain and heart injury in mice. We will now determine if the low leak mutant c-subunit mouse will prevent ischemic injury in aged mice and if it will prevent memory loss, a severe, long lasting effect of transient global ischemia in rodents and humans.
Up to $446K
2029-02-28
We'll draft the complete application against NINDS - National Institute of Neurological Disorders and Stroke's requirements, run a quality review, and email you a submission-ready PDF plus an editable Word doc within 5 business days. Most orders deliver in 24-48 hours. Flat $399, any grant size.
Detailed requirements not yet analyzed
Have the NOFO? Paste it below for AI-powered requirement analysis.
Subscribe for Pro access · Includes AI drafting + templates + PDF export
Dynamic Cognitive Phenotypes for Prediction of Mental Health Outcomes in Serious Mental Illness
NIMH - National Institute of Mental Health — up to $18.3M
COORDINATED FACILITIES REQUIREMENTS FOR FY25 - FACILITIES TO I
NCI - National Cancer Institute — up to $15.1M
Leveraging Artificial Intelligence to Predict Mental Health Risk among Youth Presenting to Rural Primary Care Clinics
NIMH - National Institute of Mental Health — up to $15.0M
Feasibility of Genomic Newborn Screening Through Public Health Laboratories
OD - NIH Office of the Director — up to $14.4M
WOMEN'S HEALTH INITIATIVE (WHI) CLINICAL COORDINATING CENTER - TASK AREA A AND A2
NHLBI - National Heart Lung and Blood Institute — up to $10.2M
Metal Exposures, Omics, and AD/ADRD risk in Diverse US Adults
NIA - National Institute on Aging — up to $10.2M