The mitosis group has identified genes and proteins involved in faithful chromosome segregation, including deciphering and reconstructing the signaling cascade of the mitotic checkpoint, the major cell cycle control pathway guarding against chromosome mis-segregation. Aneuploidy produced by chromosome missegregation has long been linked to cancer. The group’s efforts have demonstrated that low rates of missegregation drive tumorigenesis, but high rates can suppress it.
Major contributions of the neuroscience group have been in uncovering mechanism of neurodegenerative disease, especially ALS, frontal temporal degeneration (FTD) and Huntington’s disease. They demonstrated that fatal motor neuron disease disease arises from toxicity of mutant superoxide dismutase (SOD1) unrelated to its normal activity, thereby uncovering the mechanism underlying the major genetic form of Amyotrophic Lateral Sclerosis (ALS).

Most importantly, they identified that motor neuron death in inherited ALS is non-cell autonomous, requiring mutant damage to both motor neurons and the neighboring supporting cells. This finding demonstrated the feasibility of stem cell replacement of non-neuronal cells as a viable therapy in ALS. It also has wide implications for the other major neurodegenerative diseases, since the inherited forms of each are also caused by widely expressed mutant genes.

The team developed antisense DNA oligonucleotide infusion for targeted gene silencing in the nervous system. A clinical trial in ALS has been proven to be safe, and follow up trials in ALS and in Huntington’s disease are expected to initiate in 2017.
Dr. Cleveland’s research efforts are focused in two major directions:
 
 Genome rearrangement in cancer
 
 Mechanism and therapy for human neurodegenerative disease

Research

Neuron
Mitosis

Dr. Cleveland’s research efforts are focused in two major directions:

 

·         Genome rearrangement in cancer

      --  Aneuploidy and tumorigenesis

     -- Chromothripsis and chromosome rearrangement

     -- Chromosome segregation and mitotic cell cycle control

     -- Centromere identity and function

     -- Centrosomes and microtubule organization

 

·        Mechanism and therapy for human neurodegenerative disease

     -- Disease mechanism in inherited ALS and frontotemporal dementia (FTD)

§  TDP-43, FUS, C9orf72, and SOD1

§  De-mixing of TDP-43 and FUS in ALS/FTD

§  Prion-like spread in ALS

-- Gene therapy for neurodegenerative disease

§  Designer DNA drug” therapy (antisense oligonucleotides) in ALS’ FTD, Huntington’s disease and beyond

§  Development of CRISPR-Cas9 gene editing in the nervous system

§  Development of AAV9 for gene therapy in ALS and beyond

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