Assistant Professor, Department of Molecular
and Human Genetics
B.S., Howard University, 1985
Ph.D., University of Cincinnati, 1993
M.D., University of Cincinnati College of Medicine, 1993
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RESEARCH
INTERESTS:
Our laboratory is interested in understanding
the roles that members of the transforming growth factor beta (TGF-b)
superfamily play in regulating body composition, with a particular emphasis
on the mechanisms that regulate adiposity. Our approach is to modify specific
genes in mice to determine their normal functions. These genes can be either
completely inactivated or can be replaced by closely related genes. By
studying the physiologic effects of these mutations on the mice as a whole
as well as the characteristics of cells that are derived from them, we
are able to better understand the complex interrelationships of (TGF-b)
signaling, incorporating state of the art technologies to assess effects
of the mutations at the physiologic, biochemical, and molecular levels.
Activins are (TGF-b) family members that are important for many biological processes, including normal growth and development of the fetus. Mice that are completely missing one activin family member, activin bA, die shortly after birth due to a variety of birth defects. Our previous studies have demonstrated that a closely related substitute gene can be used to correct activin bA deficiency if the substitute is turned on at the correct time and in the correct location. This is an important observation, because it gives us one way to study the functions of genes that when completely inactive result in early death (such as activin bA). We have used this gene substitution ("knock-in") strategy to replace activin bA with its closely related family member, activin bB. These mice survive but grow more slowly than normal and have almost no body fat, revealing previously unrecognized roles for activins in regulating body size and composition through their influence on mitochondrial energy metabolism. The severity of these features is influenced substantially by the dose of the substitute gene. Drug-inducible Cre-recombinase technology combined with microarray analysis is also used in our laboratory to study gene function, allowing us to reversibly control the expression of any gene of interest in specific tissues or in all tissues at specific points in time and then to examine the effects of these changes on genome-wide gene expression.
Our studies have given us considerable insight into the normal roles of activin signaling and that of other TGF-b superfamily members. Moreover, the high tolerance for substitute genes observed in our studies and others may have important implications with respect to strategies for the treatment of certain genetic disorders. Our ultimate goal is to understand how TGF-b superfamily signaling may play similar roles in humans and has provided the basis for the rational design of potential drugs for the treatment of cachexia, obesity, and diabetes.Back to top
SELECTED
PUBLICATIONS:
1. Li L, Shen JJ, Huang L, Chattopadhyay A, Li Z, Shaw C, Graham
B, Brown CW (2007). Activin signaling influences body
composition by affecting mitochondrial energy metabolism, submitted.
2. Shen JJ, Huang L, Matzuk MM, Brown CW (2007). Functional inactivation of growth differentiation factor 3 results in protection from diet-induced obesity, in revision.
3. Pangas SA, Jorgez CJ, Tran M, Agno J, Li X, Brown CW, Kumar TR, Matzuk MM (2007). Intraovarian activins are required for female fertility. Mol. Endocrinol., in press.
4. Chen C, Ware SM, Houston-Hawkins DE, Matzuk MM, Shen MM, Brown CW (2006). The Vg1-related protein GDF3 regulates Nodal expression in the pre-gastrulation mouse embryo. Development 133: 319-329.
5. Kurotaki N, Shen JJ, Touyama M, Kondoh T, Visser R, Ozaki T, Nishimoto J, Shiihara T, Uetake K, Makita Y, Harada N, Raskin S, Brown CW, Hoglund P, Okamoto N, Lupski JR (2005). Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet. Med. 7: 479-483.
6. Brown CW, Li L, Houston-Hawkins DE, Matzuk MM (2003). Activins are critical modulators of growth and survival. Mol. Endocrinol. 17: 2404-2417.
7. Chang H, Brown CW, Matzuk MM (2002). Genetic analysis of the mammalian TGF-b superfamily. Endocr. Rev. 23: 787-823.
8. Transgenics in Endocrinology (2001). Matzuk MM, Brown CW, Kumar TR (eds.), Totowa, NJ: Humana Press.
9. Brown CW, Houston-Hawkins DE, Woodruff TK, Matzuk MM (2000). Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nat. Genet. 25: 453-457.
For more publications, see listing on Pub Med.
CLINICAL
INFORMATION:
Board Certifications:
American Board of Medical Genetics: Clinical Genetics
American Board of Pediatrics
Primary Focus:
Birth defects, endocrinopathies and disorders of growth.
Professional Organizations:
Member, American Society of Human Genetics
Member, Houston Medical Forum
Member, National Medical Association
Fellow, American Academy of Pediatrics
CONTACT INFORMATION:
Chester Brown, M.D., Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030, U.S.A.
Telephone: 713-798-3994
Fax: 713-798-8920
E-mail: