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Our research has been or is currently funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Heart Lung and Blood Institute (NHLBI), The LAM Foundation, the Tuberous Sclerosis Alliance, the PKD Foundation, the National Cancer Institute (NCI), the Department of Defense (DOD) as well as multiple generous donors.

Our models include cultured cells, the yeast Schizosaccharomyces pombe, genetically engineered mouse models, and xenograft mouse models. Our approaches include biochemistry, cell biology, in vivo imaging using luciferase-expressing cells, and high throughput screens with collaborators at Harvard Medical School and the Broad Institute. Our goal is to utilize the unique advantages of these different models and approaches to optimally address each individual research question.

Dr. Henske is the Director of The Center for LAM Research and Clinical Care in the Pulmonary and Critical Care Medicine (PCCM) Division of the Brigham and Women’s Hospital (BWH), which is one of the major teaching hospitals of Harvard Medical School (HMS). Dr. Henske is Professor of Medicine at Harvard Medical School. Dr. Henske sees patients with LAM at the BWH and sees patients with genito-urinary cancer through the Lank Center for Genitourinary Cancer at the Dana-Farber Cancer Institute. She is an Associate Member of the Broad Institute of MIT and Harvard.

Tuberous Sclerosis Complex (TSC) is a tumor suppressor gene syndrome with a wide spectrum of devastating clinical manifestations, many of which are age-related. Infants with TSC can develop seizures, and cardiac rhabdomyomas and cerebral cortical tubers can be present at birth. The majority of children with TSC have multiple, bilateral renal angiomyolipomas by age 10. The pulmonary manifestation of TSC, lymphangioleiomyomatosis (LAM), occurs in approximately 30% of women with TSC and typically develops in the 20’s. The other manifestations of TSC include cognitive disability, autism, subependymal giant cell astrocytomas, facial angiofibromas, renal cysts, and renal cell carcinoma. For more information about TSC, please visit the Tuberous Sclerosis Alliance website.

TSC is caused by germline mutations in the TSC1 or TSC2 gene. TSC is inherited in an autosomal dominant manner and has very high penetrance (estimated at 95%). The majority of individuals with TSC have de novo germline mutations in either TSC1 or TSC2 germline mutations without a prior family history of TSC. Both TSC1 and TSC2 are tumor suppressor genes, fitting the “two hit” model proposed by Dr. Knudson in which germline inactivation of one allele, followed by somatic inactivation of the remaining allele, is required for tumor initiation.

TSC2 encodes tuberin, a 200-kDa protein with a domain near the carboxyl terminus containing GTPase activating protein (GAP) homology. GAP proteins convert members of the Ras superfamily from their active, GTP-bound state to their inactive, GDP-bound state. TSC1 encodes hamartin, a 140-kDa protein with no homology to tuberin. Hamartin and tuberin physically interact, consistent with the similar clinical features of patients with TSC1 and TSC2 mutations. Rheb is the target of TSC2’s highly conserved GTPase-activating domain. Rheb, like other Ras family members, cycles between an active GTP-bound and an inactive GDP-bound state. TSC2 converts Rheb-GTP to Rheb-GDP, thereby inactivating Rheb. By inhibiting Rheb, the TSC1/TSC2 complex also inhibits the mammalian target of rapamycin (mTOR) complex 1 (mTORC1).

Severe renal cystic disease can occur in TSC, sometimes resembling ADPKD. Interestingly, the PKD1 and TSC2 genes are adjacent on chromosome 16p13, and contiguous deletion of both genes can lead to severe renal cystic disease in childhood. Many renal cystic diseases, including autosomal dominant polycystic kidney disease (ADPKD) and TSC, are associated with abnormalities of the primary cilium. For more information about ADPKD, please connect to the PKD Foundation.

LAM is a rare lung disease that affects almost exclusively women. LAM occurs in two forms: in association with tuberous sclerosis complex (“TSC-LAM”) and in women who do not have TSC (“sporadic LAM”). The initial symptoms of LAM can include shortness of breath, lung collapse, or pain from a renal angiomyolipoma. On high resolution CT scans, LAM is characterized by multiple thin-walled cystic lesions. Pathologically, LAM is characterized by the proliferation of benign-appearing smooth muscle cells, which thicken the alveolar wall and reduce gas exchange, and by cystic degeneration of the lungs, which can result in lung collapse. Women with LAM often become oxygen-dependent.

The term “sporadic” is used to refer to LAM that occurs in a woman who does not have a germline TSC1 or TSC2 gene mutation.

Many aspects of LAM pathogenesis, including the ability of LAM cells to metastasize to the lungs and to repopulate the lungs after lung transplantation, suggest that LAM cells behave similarly to cancer cells. However, some aspects of LAM pathogenesis are distinct from cancer, including the ability of LAM cells to degrade the normal lung resulting in lung cysts, and the benign histologic appearance of LAM cells.

The mechanisms underlying the striking female predominance of LAM are unknown. One hypothesis, based on research from our group, is that activation of MEK-dependent pathways by estrogen enhances the survival of LAM cells, allowing them to accumulate in the lungs.

Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant tumor suppressor gene syndrome characterized by hamartomas of skin follicles (fibrofolliculomas), spontaneous pneumothorax (lung collapse), and renal cell carcinoma (RCC). Unlike most other genetic disorders associated with renal tumors, BHD patients develop multiple histologic tumor types, including oncocytomas (which are considered benign) and chromophobe, clear cell and papillary carcinomas.

The clinical hallmarks of BHD: facial hamartomas (folliculomas), lung cysts, pneumothorax, and renal tumors, are similar to certain manifestations of tuberous sclerosis complex (TSC). The fact that hamartomas, lung cysts, and renal cell carcinoma can also occur in tuberous sclerosis complex (TSC) suggests that the BHD and TSC proteins may function within a common pathway.

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