Funded Research

This lab has been working on MLIV disease for nearly two decades. Slaugenhaupt identified the gene responsible for the disease, created the carrier test, and created the first MLIV mouse model.

Having established a base for understanding the neurology of the disease, they are now in the process of 1) identifying neurological pathways for treating the disease and 2) establishing the accuracy of these treatments in the MLIV models of the disease while moving ahead to testing drug and gene therapies.

Dr. Medina’s will be focusing on the role of TRPML1 (the defective protein in MLIV disease) and the kidney. In recent years, reports have described kidney disease and kidney failure in various MLIV patients in the second to the third decade of life. However, the role of TRPML1 in the kidney and the molecular mechanisms involved in kidney defects in MLIV are unknown. Thus, Dr. Medina’s lab aims to investigate the physiological relevance of TRPML1 and the consequences of its depletion in the kidney of an MLIV mouse model that well-recapitulates major hallmarks of human MLIV disease.

In addition, Medina’s laboratory utilizes High Content Screening and repurposing of clinically-approved drugs to treat lysosomal storage disorders. Recently, Medina’s lab identified two FDA-approved compounds, tamoxifen and fluoxetine, that can ameliorate disease hallmarks of Batten disease and Mucopolysaccharidosis type-IIIA, respectively. Since the mechanism of action of both drugs is at least in part through the activation of TFEB, a master gene of lysosomal function, Medina’s lab plans to test the efficacy of the compounds in cellular models of MLIV.

The Walkley lab focuses on what happens to different kinds of neurons in the central nervous system when they lack the presence of mucolipin-1, the protein missing in MLIV.  As the Walkley group is documenting the specifics of neuron abnormalities, and as they are showing pathologies in the ways that the lysosome itself is structured in MLIV cells, they are devising therapies that can help slow the progression of the disease and treat MLIV.

Dr. Futerman utilizes RNAseq studies of MLIV tissue samples to discern the most fundamental information from the genomic and proteomic data about the disease. This information illuminates pathways for treatment in MLIV tissue, and also allows him to determine in which ways MLIV is like other neurodegenerative diseases such as Parkinson’s. These disease connections aid in treatment options, research collaboration, and basic understanding of neurological diseases.

Dr. Grimm searches for small molecules that can improve the function of the TRPML1 channel that is defective in MLIV patients. The TRPML1 channel is the means by which lysosomal waste is transported out of the normal cell. Because of the defective gene in MLIV disease, this channel doesn’t work and wastes remain in cells, causing devastation.  Dr. Grimm has located drugs that can improve this process, and he is testing them to determine which could be used in patients.  In addition, he continues to use high-throughput screens to find other drugs that may be useful.

Dr. Vandenberghe has created several AAV-based vectors which are being tested in-vivo in Dr. Grishchuk’s lab. After exciting expression data from these vectors, we are now testing these vectors for efficacy to determine how beneficial they are in correcting and altering the disease state in MLIV mice.

Dr. Venkatachalam studies the synapses and proteins that control the central nervous system. By understanding how stress affects their growth, Venkatachalam documents ways to intervene in and improve synaptic function with certain drugs that improve CNS function overall.  This project has been funded by the NIH.