Madepalli Lakshmana
Florida International University, FL·Neuroscience
Cells keep themselves healthy by breaking down worn-out parts and clumps of protein through a recycling system called autophagy. Autophagy delivers this waste to lysosomes, the cell's digestive compartments.
- Fields
Neuroscience
Pharmacology
Biochemistry
- Topics
Alzheimer's disease
autophagy
cellular senescence
- Grants
- 2 known grants, through Jul 2027
What they work on
- Synthesize six sets of structurally varied TPI-132 analogs and select two with stronger activation of TFEB, a master switch for cellular recycling, plus lower toxicity and better brain penetration and solubility.
- Test the lead TPI-132 analogs in neurons from Alzheimer's model mice and patient iPSC-derived neurons for effects on senescence, dendritic spines, and amyloid-beta and tau pathology.
- Treat 3xTg and PS19 Alzheimer's model mice at 11 and 17 months with TPI-132 and analogs, measuring insulin tolerance, senescence, synapses, protein aggregates, autophagy and cognition.
- Determine whether raising or knocking down TFEB alters mu-opioid receptor desensitization, internalization and stability after morphine, fentanyl, DAMGO or methadone, using SH-SY5Y cells and striatal neurons.
- Test whether TFEB or TPI-132 changes opioid pain relief, tolerance, dependence, withdrawal and respiratory depression in TFEB-overexpressing, TFEB knockout and wild-type mice given morphine or fentanyl.
More about the research
When this system weakens, debris builds up and cells can become senescent, an aged state in which they stop working normally. The research centers on TFEB, a protein that switches on the autophagy-lysosome pathway, and on TPI-132, a small molecule the team identified that activates TFEB. The team asks whether boosting TFEB can protect the brain in two settings: Alzheimer's disease and opioid use disorder.
Why it matters
Alzheimer's disease still lacks a therapy that reliably changes its course. Current opioid use disorder drugs are limited, and overdose deaths from respiratory depression are rising. If TFEB activation proves protective, TPI-132 or improved analogs could be developed into a new class of drugs that clear toxic proteins in Alzheimer's or reduce opioid tolerance, withdrawal and breathing suppression.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Thomas Keck
Rowan University, NJ·Pharmacology
Test whether combining morphine with MP-III-024, a compound that enhances α2/α3 GABA-A receptor signaling, gives stronger pain relief without more tolerance, constipation or respiratory depression in preclinical models.
Charles France
University of Texas Health Science Center at San Antonio, TX·Pharmacology
Submit an Investigational New Drug application to the FDA for methocinnamox (MCAM), a long-acting mu-opioid receptor blocker, to prevent opioid relapse after detoxification.
Brian Ruyle
Washington University in St Louis, MO·Neuroscience·Early-career
Determine whether fentanyl acts before or after the synapse in the nucleus of the solitary tract, using a new transgenic MOR-Cre rat line with chemogenetics, optogenetics and fiber photometry to manipulate and record mu-opioid-receptor-expressing cells.
The school
Florida International University: 9 labs on PI Pages, $326M a year on research, 264 research doctorates a year.
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