Huang Lab Research
The primary interest of the Huang laboratory is to study the
molecular basis of genetic syndromes, to apply the discoveries from rare
diseases to common conditions and to develop treatments for genetic diseases.
Currently, we are focusing on the following areas:
1. The Genetic Basis of Optic Atrophy and the Potential of Inducible
Pluripotent Stem Cell (iPSC) therapy: We have worked with many families affected with
autosomal dominant inherited optic atrophy. A condition caused by mutations in
the OPA1 gene. OPA1
is encoded by the nuclear genome and functions in mitochondria. Using
electrophysiological analysis, we found that some mutations can also cause
hearing loss through asynchronous cochlear conduction and cochlear implant can
restore hearing. To study the function of OPA1
and the molecular mechanisms of optic atrophy, we created a drosophila model. We found that
mutations of Drosophila homolog of OPA1 (dOPA1) caused an increase in
reactive oxygen species (ROS) production and apoptosis. We also showed that antioxidants
could partially reverse the eye phenotype, further suggesting that ROS plays an
important role in cell death. Together, these results show that dOpa1 mutations cause cell loss by two
distinct pathogenic pathways. This study provides novel insights into the
pathogenesis of optic atrophy and demonstrates the promise of antioxidants as
therapeutic agents for this condition.
Recently, our lab is actively engaged in iPS cell therapy. We have successfully induced iPS cells
differentiation into retinal ganglion cells by chemical treatments and have
initiated the preclinical study.
2. Genetics
of Mitochondrial Diseases: Mitochondria are the powerhouse of the cell. Over 90% of the
energy required by the cell is produced in the mitochondria. Our group also
works on the genetic causes of mitochondrial disorders. We have been using exome
sequencing, cell respiration assays, and mitochondrial functional assays to
study the pathogenesis of mitochondrial diseases for the patients with novel
genetic etiology.
3. Identification of the Disease-Causing Gene for Lenz
Microphthalmia Syndrome (LMS) Using
Next Generation Sequencing Technology: LMS is a rare
condition characterized by small eyes/no eye and multiple congenital anomalies
such as small brain and mental deficiency, abnormal ear, teeth, digits,
skeletal and/or genitourinary tract. In this study, we have used a very
powerful technology, next generation sequencing, to search for the
disease-causing gene in patients with LMS. Identification of disease-causing
genes associated with LMS has
significantly facilitated our understanding of this condition
and can translate into clinical applications.
Since LMS affects multiple organ systems, understanding the gene
associated with LMS may open a window for the investigation of other common
conditions and human development. Currently, we are using iPS cell model to
study pathogenesis and function of the disease-causing gene.
4. The Role of TBX3
in Breast Cancer Development and Human Embryonic Stem (hES) Cell Differentiation: TBX3 is a T-box
transcription factor. Mutations of TBX3
cause Ulnar-Mammary syndrome, characterized by hypoplasia or absence of the
mammary glands. Our laboratory is one of the first groups to show that
overexpression of TBX3 plays an important role in breast cancer. Our study showed
that TBX3 is overexpressed in primary breast cancer tissues. Mechanistically,
we found that TBX3 interacts with HDACs and inhibit downstream target gene
expression, such as p14ARF. In addition, we found that TBX3 regulates a large
group of genes in breast cancer. Our current research aims to optimize the
clinical relevance of this data working in parallel with animal and breast
cancer tissues. Recently, we have also found that TBX3 plays a very important
role in hES cell differentiation. This finding may further our understanding of
TBX3 function.
