Major Research Areas
Researchers in the College of Graduate Studies focus their efforts where it truly matters—on the diseases and illnesses that affect many people. Much of our research activity is grouped into four areas of concentration: cancer; infectious diseases; disorders of the nervous system; and diabetes, metabolic disorders and cardiovascular diseases.
Frank A Middleton, PhD
- Associate Professor of Neuroscience and Physiology
- Associate Professor of Biochemistry and Molecular Biology
- Associate Professor of Psychiatry and Behavioral Sciences
Research Programs and Affiliations
- Biomedical Sciences Program
- Center for Neuropsychiatric Genetics
- Center for Psychiatric Neuroimaging
- Medical Genetics Research Center
- Neuroscience Program
- Neuroscience and Physiology
- Physiology Program
- Parkinson's disease
- Bipolar disorder
- Velocardiofacial syndrome
Molecular basis of cortical-basal ganglia and cortical-cerebellar circuit formation and dysfunction in neurological and psychiatric disease.
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Research in the Middleton lab focuses on defining substrates of normal and abnormal motor and cognitive function. This is accomplished by performing high-throughput genetic, epigenetic, and functional genomic studies involving human subjects or animal and cellular models of various neuropsychiatric, neurodegenerative, and addictive disorders. The specific disorders of most interest include autism, schizophrenia, ADHD, Parkinson's disease, alcohol abuse, and traumatic brain injury. In addition to the use of similar analytical methods to study these conditions, another common underlying theme is the attempt to define their relationship to neural-immune responses. Thus, the neural-immune axis forms a major lab interest as well, and this has been pursued through several collaborative efforts in studies of central and peripheral inflammatory and immune system alterations in these and other conditions, such as lupus, multiple sclerosis, and Zika virus infection. While in the past, it might have been nearly impossible for one lab to simultaneously pursue research on so many different topics, with the advent of modern bioinformatic tools and systems biological methods, these integrated approaches are now seen as highly valuable. Indeed, comparisons across disorders can help define the specificity of the changes that are seen and may lead to the identification of novel biomarkers or therapeutic agents. As examples, recent publications from the lab describe several novel discoveries of DNA mutations causally linked to schizophrenia, or microRNA biomarkers in peripheral blood or saliva that are strongly associated with alcohol abuse or autism spectrum disorder. Students and postdoctoral fellows who are interested in the research performed in the lab will likely become well-versed in next generation sequencing, comparative anatomical analysis, and statistical data mining.
Cohen OS, Weickert TW, Hess JL, Paish LM, McCoy SY, Rothmond DA, Galletly C, Liu D, Weinberg DD, Huang XF, Xu Q, Shen Y, Zhang D, Yue W, Yan J, Wang L, Lu T, He L, Shi Y, Xu M, Che R, Tang W, Chen CH, Chang WH, Hwu HG, Liu CM, Liu YL, Wen CC, Fann CS, Chang CC, Kanazawa T, Middleton FA, Duncan TM, Faraone SV, Weickert CS, Tsuang MT, Glatt SJ. A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples. Mol Psychiatry. 2016 Jul;21(7):975-82. PubMed PMID: 26347318
Hicks SD, Ignacio C, Gentile K, Middleton FA. Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment. BMC Pediatr. 2016 Apr 22;16(1):52. PubMed PMID: 27105825
Ignacio C, Hicks SD, Burke P, Lewis L, Szombathyne-Meszaros Z, Middleton FA. Alterations in serum microRNA in humans with alcohol use disorders impact cell proliferation and cell death pathways and predict structural and functional changes in brain. BMC Neurosci. 2015 Sep 5;16:55. PubMed PMID: 26341662
Kates WR, Olszewski AK, Gnirke MH, Kikinis Z, Nelson J, Antshel KM, Fremont W, Radoeva PD, Middleton FA, Shenton ME, Coman IL. White matter microstructural abnormalities of the cingulum bundle in youths with 22q11.2 deletion syndrome: associations with medication, neuropsychological function, and prodromal symptoms of psychosis. Schizophr Res. 2015 Jan;161(1):76-84. PubMed PMID: 25066496
Afshari P, Myles-Worsley M, Cohen OS, Tiobech J, Faraone SV, Byerley W, Middleton FA. Characterization of a novel mutation in SLC1A1 associated with schizophrenia. Mol Neuropsychiatry. 2015;1(3):125-144. PubMed PMID: 26380821
Radoeva PD, Coman IL, Salazar CA, Gentile KL, Higgins AM, Middleton FA, Antshel KM, Fremont W, Shprintzen RJ, Morrow BE, Kates WR. Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes. Psychiatr Genet. 2014 Dec;24(6):269-72. PubMed PMID: 25325218
Melhem NM, Lu C, Dresbold C, Middleton FA, Klei L, Wood S, Faraone SV, Vinogradov S, Tiobech J, Yano V, Roeder K, Byerley W, Myles-Worsley M, Devlin B. Characterizing runs of homozygosity and their impact on risk for psychosis in a population isolate. Am J Med Genet B Neuropsychiatr Genet. 2014 Sep;165B(6):521-30. PubMed PMID: 24980794.
Zhang-James Y, Yang L, Middleton FA, Yang L, Patak J, Faraone SV. Autism-related behavioral phenotypes in an inbred rat substrain. Behav Brain Res. 2014 Aug 1;269:103-14. doi: 10.1016/j.bbr.2014.04.035. Epub 2014 Apr 26. PubMed PMID
Perlstein MD, Chohan MR, Coman IL, Antshel KM, Fremont WP, Gnirke MH, Kikinis Z, Middleton FA, Radoeva PD, Shenton ME, Kates WR. White matter abnormalities in 22q11.2 deletion syndrome: preliminary associations with the Nogo-66 receptor gene and symptoms of psychosis. Schizophr Res. 2014 Jan;152(1):117-23. PubMed PMID: 24321711
Ignacio C, Mooney SM, Middleton FA. Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment. Front Pediatr. 2014 Sep 24;2:103. PubMed PMID: 25309888
Myles-Worsley M, Tiobech J, Browning SR, Korn J, Goodman S, Gentile K, Melhem N, Byerley W, Faraone SV, Middleton FA. Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. Am J Med Genet B Neuropsychiatr Genet. 2013 Mar;162B(2):87-95. PubMed PMID: 23341099
Hicks SD, Lewis L, Ritchie J, Burke P, Abdul-Malak Y, Adackapara N, Canfield K, Shwarts E, Gentile K, Meszaros ZS, Middleton FA. Evaluation of cell proliferation, apoptosis, and DNA-repair genes as potential biomarkers for ethanol-induced CNS alterations. BMC Neurosci. 2012 Oct 25;13:128. PubMed PMID: 23095216