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Email

hzoghbi@bcm.edu

Positions

Professor

Molecular and Human Genetics
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Investigator

Howard Hughes Medical Institute

Director

Jan and Dan Duncan Neurological Research Institute
Texas Children’s Hospital

Professor

Pediatrics - Neurology and Developmental Neuroscience
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Professor

Neuroscience
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Professor

Program in Integrative Molecular and Biomedical Sciences
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Professor

Program in Developmental Biology
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Professor

Program in Translational Biology & Molecular Medicine
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Ralph D. Feigin, M.D. Endowed Chair

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Houston, Texas United States

Member

Dan L Duncan Comprehensive Cancer Center
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Houston, Texas United States

Addresses

²ÝÁñÉçÇøÈë¿Ú Department of Pediatrics (Office)

Jan and Dan Duncan NRI
1250 Moursund St., Suite N1350
Houston, TX 77030
United States
Phone: (713) 798-6558

²ÝÁñÉçÇøÈë¿Ú Department of Pediatrics (Clinic)

Jan and Dan Duncan NRI
1250 Moursund St., Suite N1350
Houston, TX 77030
United States
Phone: (713) 798-6558

Education

Post-Doctoral Fellowship at Baylor College Of Medicine

01/1985 - Houston, Texas United States

MD from Meharry Medical College

01/1979 - Nashville, Tennessee United States

BS from American University Of Beirut

01/1976 - Beirut, Lebanon

Certifications

General Pediatrics

American Board of Pediatrics

Honors & Awards

Elaine Redding Brinster Prize in Science or Medicine

Penn Institute for Regenerative Medicine at the University of Pennsylvania (09/2022)

Kavli Prize in Neuroscience

The Norwegian Academy of Science and Letters (06/2022)

Brain Prize

Lunbeckfonden (01/2020)

Victor McKusick Leadership Award

American Society of Human Genetics (09/2019)

Norman J. Siegel Award

American Pediatric Society (01/2019)

National Academy of Inventors

01/2019

Member of American Association of Arts and Sciences

01/2018

National Order of the Cedar, Lebanon

Lebanon (01/2018)

Breakthrough Prize in Life Sciences

01/2017

Canada Gairdner International Award

01/2017

Jesse Stevenson Kovalenko Medal

01/2016

Vanderbilt Prize in Biomedical Science

01/2015

Shaw Prize in Life Science and Medicine

01/2016

Honorary Doctorate of Science

Yale University (01/2014)

March of Dimes Prize in Developmental Biology

March of Dimes (01/2014)

Sckolnick Prize

McGovern Institute for Brain Research at MIT (01/2014)

The Pearl Meister Greengard Prize

The Rockefeller University (01/2013)

Dickson Prize in Medicine

University of Pittsburg School of Medicine (01/2013)

Gruber Prize in Neuroscience

01/2011

International Rett Syndrome Foundation's Circle of Angels Research Award

01/2009

Vilcek Prize for Biomedical Research

01/2009

National Academy of Sciences

Elected

01/2004

Institute of Medicine, National Academy of Sciences

Elected

01/2000

Texas Women's Hall of Fame Award

Texas Governor's Commission for Women

Abilene, TX (01/2008)

Bernard Sachs Award

Child Neurology Society

01/2001

Sidney Carter Award

American Academy of Neurology

01/1998

Soriano Award

The American Neurological Association

01/1998

Javits Award

NINDS Council, National Institutes of Health

01/1998

E. Mead Johnson Award

Society of Pediatric Research

01/1996

Kilby Award for Extraordinary Contributions to Society

01/1995

Bristol-Myers Squibb Neuroscience Distinguished Achievement Award

01/2006

Marion Spencer Fay Award

Drexel University College of Medicine

Philadelphia, PA (01/2009)

Robert J. and Claire Pasarow Foundation Award in Neuropsychiatry

Los Angeles , CA (01/2007)

Neuronal Plasticity Prize

IPSEN Foundation

Lisbon, Portugal (01/2004)

Marta Philipson Award in Pediatrics

Philipson Foundation for Research

Stockholm, Sweden (01/2004)

Honorary Doctorate of Science

Meharry Medical School

Nashville, TN (01/2008)

Honorary Doctorate of Science

Middlebury College

Middlebury, VT (01/2007)

Professional Interests

• Pathogenesis of neurodegenerative disease
• Rett syndrome
• Normal neurodevelopment
• Ataxin-1
• Akt
• Mouse models

Professional Statement

My laboratory’s research is rooted in my early clinical encounters with patients suffering rare and enigmatic disorders. One memorable patient suffered Rett Syndrome; another was part of a family that suffered a neurodegenerative disease that struck each successive generation at younger ages. Our investigations into the pathogenesis of these two diseases have influenced our understanding of basic neurobiology and more common disorders. Conversely, our foray into fundamental neurodevelopmental processes governed by Atonal homolog 1 has had unexpected ramifications for our understanding of (and potential therapies for) several diseases, from deafness and medulloblastoma to sudden infant death syndrome. Polyglutamine Pathogenesis and Neurodegeneration. We co-discovered the gene for spinocerebellar ataxia type 1 (SCA1) in 1993 with Dr. Harry Orr at the University of Minnesota and have been collaborating to understand the disease mechanism. Our genetic studies in mice and, in collaboration with Juan Botas, in fruit flies led us to propose that the polyglutamine tract stabilizes Ataxin-1 increasing its levels and interactions and causing toxicity due to its enhanced function. Consistent with this we discovered that a 30-50% increase in wild-type Ataxin-1 causes cerebellar degeneration and ataxia in mice. We also discovered that the enhanced function of mutant Ataxin-1 with its native partner Capicua drives the cerebellar ataxia. Further, we discovered that reducing Ataxin-1 in the cerebellum is a viable therapeutic strategy, but that for other vulnerable brain regions the pathogenic mechanism is distinct. Interestingly, we learned that loss of Ataxin-1 and subsequently the repressor activity of the Ataxin-1-CIC complex leads to upregulation of Bace1 and increased risk of Alzheimer pathology in the forebrain. Our current studies are focused on understanding the mechanisms driving the regional vulnerability in SCA1. Inspired by our work on SCA1 and the importance of Ataxin-1 levels for brain health, we have pursued cross-species studies to identify modulators of APP, tau and alpha-synuclein, proteins that drive degeneration in Alzheimer's and Parkinson's disease. Atoh1 (aka Math1) and Neurodevelopment. We identified the mouse homolog of the Drosophila gene atonal, which controls the development of the fly’s chordotonal organs. We showed Atoh1 null mice lack cerebellar granule neurons, pontine neurons, hair cells in the vestibular and auditory systems, D1 interneurons of the spinocerebellar tracts, Merkel cells, and intestinal secretory cells. Atoh1 controls the genesis and/or differentiation of multiple components of the conscious and unconscious proprioceptive pathway and the neurons critical for interoception, chemosensitivity and neonatal breathing. We are interested in understanding how this one gene guides the differentiation of diverse neurons from one progenitor population. To this end, we are pursuing single cell sequencing and detailed molecular studies during development. Rett Syndrome. We discovered that Rett syndrome is caused by mutations in the X-linked methyl-CpG–binding protein 2 (MECP2). Our mouse model studies led to the definition of clinical phenotypes not previously appreciated in MeCP2 disorders and revealed that neurons are quite sensitive to having just slightly too much or too little MeCP2. In collaboration with Jianrong Tang (BCM), we found that forniceal deep brain stimulation restored hippocampal learning and plasticity. Using a MECP2 duplication mouse model, we found that normalizing MeCP2 levels using antisense oligonucleotides reverse the symptoms including late-onset seizures in adult mature animals. More recently, we discovered that presymptomatic training of Rett mice improved their performance, delayed disease onset by months and improved neuronal morphology and physiology. Our work is now focused on three main areas: the identification of a biomarker that serves as a proxy for MeCP2 levels, understanding of MeCP2 regulation and the network dysfunction in Rett syndrome, with the ultimate goal of targeting regulators of MeCP2 levels as well as network modulation as potential therapies.

Websites

Selected Publications

• Achilly N, Wang W, Zoghbi HY "Presymptomatic training mitigates functional deficits in Rett syndrome mice.." Nature. 2021;592:596-600.
• Nitschke L, Tewari A, Coffin SL, Xhako E, Pang K, Gennarino VA, Johnson JL, Blanco FA, Liu Z, Zoghbi HY "miR760 regulates ATXN1 levels via interaction with its 5’ untranslated region." Genes Dev. 2020;34:1147-1160.
• Suh J, Romano DM, Nitschke L, Herrick SP, DiMarzio BA, Dzhala V, Bae JS, Oram MK, Zheng Y, Hooli B, Mullin K, Gennarino VA, Wasco W, Schmahmann JD, Albers MW, Zoghbi HY, Tanzi RE. "." Cell. 2019;178:1159-1175.e17.. Pubmed PMID:
• Van der Heijden ME, Zoghbi HY "." Elife. 2018;7:e38455. Pubmed PMID: