The long-term goal of this project is to identify pharmacological treatments for diseases in which mitochondrial dysfunction is a critical component. Examples include acute organ failures (e.g. traumatic brain disorder (VETERAN), stroke (VETERAN), and kidney), chronic diseases (e.g. PTSD (VETERAN), diabetes, neurodegenerative) and mitochondrial diseases. Because there are no truly effective therapies that promote cell and organ repair/regeneration, and recovery of organ function in acute/chronic diseases, drug therapies are desperately needed. Mitochondrial dysfunction with the loss of ATP occurs after oxidative stress during ischemia/reperfusion (I/R) and leads to cell injury and death, and organ failure. Cells replace old and dysfunctional mitochondria through mitochondrial biogenesis (MB). Consequently, we started a drug discovery program in MB and recently identified the 5-HT1F receptor as a novel target for MB. The 5-HT1F receptor is a lesser studied 5-HT receptor found in the CNS and other tissues, including the kidney. LY344864, a potent and selective 5-HT1F agonist, induced MB in renal proximal tubular cells (RPTC) at 1-100 nM in 24 hr. Knockdown of the 5-HT1F receptor using siRNA confirmed LY334864 produced MB through the 5-HT1F receptor. Experiments in nave mice documented that LY344864 induced MB in the kidney within 24 hr. A proof-of-concept experiment determined that LY344864 accelerated recovery of renal function after I/R-induced acute kidney injury (AKI) in mice. These exciting results support the hypothesis that 5-HT1F agonist-induced MB post-AKI injury restores mitochondrial function and stimulates cell and renal repair/regeneration.
Specific Aim 1 : Elucidate the signaling pathway by which 5-HT1F receptor agonists LY344864 and lasmiditan induce MB in RPTC. Lasmiditan, a newer 5-HT1F receptor agonist undergoing clinical trials for the treatment of migraines, tested positive in our MB screening assay. Because lasmiditan is likely to become a FDA-approved drug and could be repurposed, we will study the signaling pathway by which LY344864 and lasmiditan induce MB.
Specific Aim 2 : Determine renal mitochondrial function and homeostasis, and MB in recently developed 5-HT1F receptor knockout mice and wild-type mice of increasing age.
Specific Aim 3 : Elucidate the role of the 5-HT1F receptor in AKI and the recovery thereof and the efficacy of LY344864 and lasmiditan in promoting MB and accelerating the recovery of renal function in a mouse model of renal I/R-induced AKI. These studies will examine 1) a new target, 5-HT1F receptor, for MB, 2) a novel pathway of MB, 3) the role of 5- HT1F receptor in mitochondrial function and homeostasis, and 4) the efficacy of 5-HT1F receptor agonists in the treatment of acute organ injury, specifically AKI, using cellular and in vivo models. A combination of molecular biological, biochemical, and pharmacological approaches and a knockout mouse will be used to complete the aims identified above. Ultimately, these studies may lead to new therapeutic approaches to increase cell and organ survival and function in numerous pathologic situations.
Acute kidney injury remains an enormous public health concern as no effective therapies have proven useful after renal injury has occurred. Mitochondrial biogenesis, the process of replacing dysfunctional mitochondria with new mitochondria, represents a novel approach to stimulate cell and organ repair/regeneration after renal injury, and accelerate the return of renal function. We will study the mechanism by which 5-HT1F receptor agonists induce mitochondrial biogenesis and the efficacy of these drugs in treating acute kidney injury. This novel approach may not only lead to new therapeutic approaches to treat acute kidney injury but also other acute organ failures (e.g. traumatic brain injury (VETERAN), stroke, (VETERAN) and myocardial infarction), chronic organ failures (e.g. post-traumatic stress disorder (VETERAN), metabolic syndrome, neurodegenerative diseases) and mitochondrial diseases.
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