Biswarathan Ramani, MD, PhD

A photo of Dr. Ramani
Assistant Professor
Primary Thematic Area
Neurobiology
M_Path-Anatomic Path
Secondary Thematic Area
Human Genetics
Research Summary
We study mechanisms of protein homeostasis in neurodegeneration, integrating high-throughput CRISPR functional genomics and other multiomic approaches with iPSC and mouse models of disease. 
Most neurodegenerative disorders are marked by the age-dependent accumulation of misfolded and aggregated proteins in the brain, particularly within neurons. Our laboratory seeks to understand how the neuronal protein homeostasis (proteostasis) network defends against age-related neurodegenerative diseases. These diseases include repeat expansion diseases (Huntington's disease, spinocerebellar ataxia, neuronal intranuclear inclusion disease), amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. We integrate an interdisciplinary approach of high-throughput CRISPR-based functional genomics, transcriptomics, microscopy/imaging, proteomic, and biochemical techniques to study disease mechanisms in cell models (including iPSC-derived neurons), mouse models, and human neuropathologic tissues.  We recently developed a highly scalable in vivo pooled CRISPR perturbation system, allowing us to systematically evaluate the role of the neuronal proteostasis network in different disease models and in different neuronal populations.  
 
Research Projects
1. Mapping the neuronal proteostasis network in the Huntington's disease, neuronal intranuclear inclusion disease, and frontotemporal dementia/amyotrophic lateral sclerosis.
2. Understanding the molecular and biochemical/biophysical basis of chaperone selectivity for different disease-associated proteins
3. Dissecting regional and cell-type specific vulnerability in diseases caused by chaperone mutations
4. Elucidating nuclear proteostasis pathways and mechanisms of nuclear proteotoxicity in repeat expansion diseases
5. Defining genetic modifiers and mechanisms of TDP-43-mediated toxicity in aging and neurodegeneration. 

Publications

Targeted Next-Generation Sequencing Reveals Divergent Clonal Evolution in Components of Composite Pleomorphic Xanthoastrocytoma-Ganglioglioma.

Journal of neuropathology and experimental neurology

Lucas CG, Davidson CJ, Alashari M, Putnam AR, Whipple NS, Bruggers CS, Mendez JS, Cheshier SH, Walker JB, Ramani B, Cadwell CR, Sullivan DV, Lu R, Mirchia K, Van Ziffle J, Devine P, Goldschmidt E, Hervey-Jumper SL, Gupta N, Oberheim Bush NA, Raleigh DR, Bollen A, Tihan T, Pekmezci M, Solomon DA, Phillips JJ, Perry A

Intracranial mesenchymal tumor with FET-CREB fusion - a unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

Brain pathology (Zurich, Switzerland)

Sloan EA, Chiang J, Villanueva-Meyer JE, Alexandrescu S, Eschbacher JM, Wang W, Mafra M, Ud Din N, Carr-Boyd E, Watson M, Punsoni M, Oviedo A, Gilani A, Kleinschmidt-DeMasters BK, Coss DJ, Lopes MB, Raffel C, Berger MS, Chang S, Reddy A, Ramani B, Ferris SP, Lee JC, Hofmann JW, Cho SJ, Horvai AE, Pekmezci M, Tihan T, Bollen AW, Rodriguez F, Ellison DW, Perry A, Solomon DA

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta neuropathologica communications

Lucas CG, Gupta R, Doo P, Lee JC, Cadwell CR, Ramani B, Hofmann JW, Sloan EA, Kleinschmidt-DeMasters BK, Lee HS, Wood MD, Grafe M, Born D, Vogel H, Salamat S, Puccetti D, Scharnhorst D, Samuel D, Cooney T, Cham E, Jin LW, Khatib Z, Maher O, Chamyan G, Brathwaite C, Bannykh S, Mueller S, Kline CN, Banerjee A, Reddy A, Taylor JW, Clarke JL, Oberheim Bush NA, Butowski N, Gupta N, Auguste KI, Sun PP, Roland JL, Raffel C, Aghi MK, Theodosopoulos P, Chang E, Hervey-Jumper S, Phillips JJ, Pekmezci M, Bollen AW, Tihan T, Chang S, Berger MS, Perry A, Solomon DA

Gliomas arising in the setting of Li-Fraumeni syndrome stratify into two molecular subgroups with divergent clinicopathologic features.

Acta neuropathologica

Sloan EA, Hilz S, Gupta R, Cadwell C, Ramani B, Hofmann J, Kline CN, Banerjee A, Reddy A, Oberheim Bush NA, Chang S, Braunstein S, Chang EF, Raffel C, Gupta N, Sun PP, Kim JYH, Moes G, Alva E, Li R, Bruggers CS, Alashari M, Wetmore C, Garg S, Dishop M, Van Ziffle J, Onodera C, Devine P, Grenert JP, Lee JC, Phillips JJ, Pekmezci M, Tihan T, Bollen AW, Berger MS, Costello JF, Perry A, Solomon DA

The Right Frame.

Journal of hospital medicine

Minter DJ, Geha RM, Boslett BA, Chung SA, Ramani B, Manesh R