About Us
Our Research
Our research is focused on human diseases caused by defects in the cytoskeleton. The cytoskeleton is a key structural component of all cells that enables fundamental processes like growth, survival and movement. Abnormal remodeling of the cytoskeleton is prevalent across human diseases, including cancer and neurodegeneration.
Our lab has generated clinically relevant human iPSC models to study the cell biology and pathology of cytoskeletal protein aggregates resulting from genetic mutations. We complement our human cell-based models with in vivo approaches aimed at preventing disease progression through the restoration of cytoskeletal proteostasis.
Specifically, we focus on intermediate filaments (IFs), which form dynamic cytoskeletal networks critical for mechanical integrity, stress regulation, transcription, and proper organelle localization. IF gene mutations cause over 80 human diseases that affect nearly every organ system and tissue type. Our current projects seek to advance the biology and therapy of two IF diseases that affect the nervous system: Alexander Disease (AxD) and Giant Axonal Neuropathy (GAN).
Alexander Disease
Alexander Disease (AxD) is a leukodystrophy caused by mutations in the GFAP gene, which encodes glial fibrillary acidic protein - the major intermediate filament protein expressed in astrocytes of the nervous system. Our lab studies the structure, function and regulation of the GFAP protein. We use multidisciplinary approaches to investigate the molecular mechanisms, including post-translational modifications (PTMs), leading to GFAP misfolding and accumulation in AxD astrocytes. Our goal is to advance small molecule-based approaches for restoring and maintaining proper GFAP structure and function.
Previously we discovered abnormal phosphorylation of GFAP at serine-13 (S13) in AxD patient brain and demonstrated that S13 is critical for GFAP filament assembly and maintenance of proper GFAP organization in cells. Pharmacological targeting of GFAP phosphorylation is a viable strategy to mitigate GFAP misfolding independent of the AxD mutation. As there are over 160 distinct missense mutations in GFAP, PTM-based approaches are promising as GFAP mutation-agnostic AxD treatments. Our current projects focus on targeting the major pathology-driving GFAP S13 kinase.
Giant Axonal Neuropathy
Giant axonal neuropathy (GAN) is a hereditary neurodegenerative disease affecting the peripheral and the central nervous system. GAN is caused by loss-of-function mutations in the gene KLHL16, which encodes the protein gigaxonin. Gigaxonin promotes the degradation and turnover of intermediate filaments. In the absence of functional gigaxonin, intermediate filament proteins accumulate and aggregate in GAN patient cells, impeding major cellular functions and leading to progressive axonal degeneration of neurons. Our research goals are to block IF accumulation and identify promising targets for neuronal regeneration in GAN patients.
We use patient-derived iPSC-neuron models of GAN to conduct drug screening studies for small molecules that can alleviate GAN cellular phenotypes. By combining our drug screens with multi-omics analysis of GAN patient cells, we recently identified retinoic acid signaling as a therapeutic target in GAN. Using and integrated platform of human cells and novel humanized mouse models we are currently targeting retinoic acid receptors and binding proteins in GAN.