David Housman

The research goals of my laboratory group involve the utilization of genetic approaches to the identification of mechanistic bases of human disease pathology and the utilization of this knowledge to develop effective strategies for intervention in human disease. Our efforts are focused in three major disease areas: trinucleotide repeat disorders particularly Huntington’s disease (HD), cancer and cardiovascular disease.


Huntington’s disease

Our current research goals include identifying modifier genes which are responsible for variation in age of onset for HD. Prospective studies on extended HD families demonstrate that, other than the length of the CAG repeat sequence, modifier genes contribute significantly to determining the age of onset for HD. We are currently pursuing genetic linkage and association studies designed to identify these genes. In parallel, we are carrying out studies to identify genes which contribute to the timing of disease onset in mouse model systems for HD. We have also developed a series of model systems for the pathological effects of expanded polyglutamine repeats in Huntington’s disease. Using these systems we have achieved the following goals:

  1. Developed genetic suppressors of the pathological effects of expanded polyglutamines and assessed the mode of action of these suppressors.
  2. Isolated small molecules which inhibit the pathological effects of expanded polyglutamines.
  3. Identified a pathway to pathology which involves transcriptional disregulation and the inhibition of histone deacetylase activities.

Our current goals are focused on the identification and development of small molecules which show promise for therapeutic intervention in HD.

Cancer

We have focused on several cancers including Wilms tumor, glioblastoma and melanoma, in which analysis of genetic alterations in germline DNA or in specific tumors identify pathways of particular significance to tumorigenesis.

Wilms tumor

My laboratory has been very active in the study of the WT1 tumor suppressor gene demonstrating its key role in tumorigneesis and kidney and urogeneital development. Most recently, we have focused on the role of the WT1 gene in hematopoiesis. WT1 has been utilized as a marker and proposed as a target for therapy for leukemia. We studied murine hematopoietic cells in which the WT1 gene has been inactivated by homologous recombination. We have found that cells lacking WT1 show deficits in hematopoietic stem cell function. We are currently exploring the impact of compromise to WT1 function on both normal and leukemic cells with the goal of gaining further understanding of the utility of WT1 as a marker and a target in therapy for leukemia.

Glioblastoma

We have focused on the receptor tyrosine kinase, c-Ros, which we have shown to be activated in a novel manner in glioblastoma. Through the characterization of a microdeletion on 6q22 in a glioblastoma, c-Ros can be activated via fusion to a novel Golgi apparatus-associated protein, Fig. The fused protein product (Fig-Ros) displays intrinsic kinase activity and is a potent oncogene. The transforming potential of the Fig-Ros fusion product resides in its ability to interact with and become localized to the Golgi apparatus. We are currently exploring the mechanisms by which a Golgi localized activated oncogene can cause cell transformation, and are initiating studies to identify small molecules which may serve as probes for Ros function in glioblastoma and the basis for possible therapeutic intervention for this tumor.

Melanoma

The goal of this project is to utilize high throughput genomic methodologies to identify genes contributing to various aspect of tumorigenesis in the InkD2/3 -/- tyr-rasV12G mouse melanoma model system. Our goal is to identify genes which contribute to the development of melanoma through studies of LOH in tumors and the mapping of modifier genes which accelerate or retard tumorigenesis in this model.

Cardiovascular disease

We are currently taking two major approaches to identifying genes which are significant contributors to cardiovascular disease. One approach involves population based association studies in which we are testing the association of specific SNP genotypes and haplotypes to cardiovascular disease and associated phenotypes. Our second approach involves proteomic analysis in a mouse model system. These studies currently focus on a mouse model for the cardiac pathology observed in myotonic dystrophy, We have utilized a proteomic approach including two dimensional gel electrophoresis and mass spectrometry to identify polypeptides which are altered in mobility in the hearts of mice deficient in the DMPK protein kinase, a gene whose expression is compromised in myotonic dystrophy and whose absence causes significant cardiac pathology in mice which lack this kinase. The goal of these studies is to determine the pathway to cardiac pathology which begins with the absence of function of the DMPK kinase and through this understanding elucidate the signaling pathways involving the DMPK kinase. Our further goal is to generalize this approach to other mouse models of cardiac pathology.


Shearman AM, Cooper JA, Kotwinski PJ, Miller GJ, Humphries SE, Ardlie KG, Jordan B, Irenze K, Lunetta KL, Schuit SC, Uitterlinden AG, Pols HA, Demissie S, Cupples LA, Mendelsohn ME, Levy D, Housman DE. Estrogen Receptor {alpha} Gene Variation Is Associated With Risk of Myocardial Infarction in More Than Seven Thousand Men From Five Cohorts. Circ Res. 2006 Feb 16

Peter I, Shearman AM, Vasan RS, Zucker DR, Schmid CH, Demissie S, Cupples LA, Kuvin JT, Karas RH, Mendelsohn ME, Housman DE, Benjamin EJ. Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women. Am J Hypertens. 2005 Nov;18(11):1388-95

Peter I, Shearman AM, Zucker DR, Schmid CH, Demissie S, Cupples LA, Larson MG, Vasan RS, D'Agostino RB, Karas RH, Mendelsohn ME, Housman DE, Levy D. Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study. J Hypertens. 2005 Dec;23(12):2193-200

Shearman AM, Cooper JA, Kotwinski PJ, Humphries SE, Mendelsohn ME, Housman DE, Miller GJ. Estrogen receptor alpha gene variation and the risk of stroke. Stroke. 2005 Oct;36(10):2281-2

Fox CS, Yang Q, Cupples LA, Guo CY, Atwood LD, Murabito JM, Levy D, Mendelsohn ME, Housman DE, Shearman AM. Sex-specific association between estrogen receptor-alpha gene variation and measures of adiposity: the Framingham Heart Study. J Clin Endocrinol Metab. 2005 Nov;90(11):6257-62

Prawitt D, Enklaar T, Gartner-Rupprecht B, Spangenberg C, Lausch E, Reutzel D, Fees S, Korzon M, Brozek I, Limon J, Housman DE, Pelletier J, Zabel B. Microdeletion and IGF2 loss of imprinting in a cascade causing Beckwith-Wiedemann syndrome with Wilms' tumor. Nat Genet. 2005 Aug;37(8):785-6

Shearman AM, Demissie S, Cupples LA, Peter I, Schmid CH, Ordovas JM, Mendelsohn ME, Housman DE. Tobacco smoking, estrogen receptor alpha gene variation and small low density lipoprotein level. Hum Mol Genet. 2005 Aug 15;14(16):2405-13

Demissie S, Cupples LA, Shearman AM, Gruenthal KM, Peter I, Schmid CH, Karas RH, Housman DE, Mendelsohn ME, Ordovas JM. Estrogen receptor-alpha variants are associated with lipoprotein size distribution and particle levels in women: the Framingham Heart Study. Atherosclerosis. 2006 Mar;185(1):210-8

Yang Q, Lai CQ, Parnell L, Cupples LA, Adiconis X, Zhu Y, Wilson PW, Housman DE, Shearman AM, D'Agostino RB, Ordovas JM. Genome-wide linkage analyses and candidate gene fine mapping for HDL 3 cholesterol: the Framingham Study. J Lipid Res. 2005 Jul;46(7):1416-25.

Prawitt D, Enklaar T, Gartner-Rupprecht B, Spangenberg C, Oswald M, Lausch E, Schmidtke P, Reutzel D, Fees S, Lucito R, Korzon M, Brozek I, Limon J, Housman DE, Pelletier J, Zabel B. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4085-90.

Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE, Roark M, Washington SL, Maxwell MM, Marsh JL, Thompson LM, Wanker EE, Young AB, Housman DE, Bates GP, Sherman MY, Kazantsev AG. A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):892-7

McCarty JH, Lacy-Hulbert A, Charest A, Bronson RT, Crowley D, Housman D, Savill J, Roes J, Hynes RO. Selective ablation of alphav integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death. Development. 2005 Jan;132(1):165-76

Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, Housman DE, Graybiel AM. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004 Sep;10(9):982-6

Shearman AM, Karasik D, Gruenthal KM, Demissie S, Cupples LA, Housman DE, Kiel DP. Estrogen receptor beta polymorphisms are associated with bone mass in women and men: the Framingham Study. J Bone Miner Res. 2004 May;19(5):773-81

Natoli TA, Alberta JA, Bortvin A, Taglienti ME, Menke DB, Loring J, Jaenisch R, Page DC, Housman DE, Kreidberg JA. Wt1 functions in the development of germ cells in addition to somatic cell lineages of the testis. Dev Biol. 2004 Apr 15;268(2):429-40.

Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G, Roberts SA, Gayan J, Brocklebank D, Cherny SS, Cardon LR, Gray J, Dlouhy SR, Wiktorski S, Hodes ME, Conneally PM, Penney JB, Gusella J, Cha JH, Irizarry M, Rosas D, Hersch S, Hollingsworth Z, MacDonald M, Young AB, Andresen JM, Housman DE, De Young MM, Bonilla E, Stillings T, Negrette A, Snodgrass SR, Martinez-Jaurrieta MD, Ramos-Arroyo MA, Bickham J, Ramos JS, Marshall F, Shoulson I, Rey GJ, Feigin A, Arnheim N, Acevedo-Cruz A, Acosta L, Alvir J, Fischbeck K, Thompson LM, Young A, Dure L, O'Brien CJ, Paulsen J, Brickman A, Krch D, Peery S, Hogarth P, Higgins DS Jr, Landwehrmeyer B; U.S.-Venezuela Collaborative Research Project. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3498-503.